ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР

Изобретение относится к области биотехнологии, в частности к химерному антигенному рецептору (CAR), который связывает антиген созревания В-клеток (BCMA), а также к экспрессионной конструкции нуклеиновой кислоты и клетке, содержащим молекулу нуклеиновой кислоты, кодирующую указанный CAR. Также раскрыт вектор, содержащий вышеуказанную экспрессионную конструкцию. Изобретение также относится к способу получения цитолитической иммунной клетки, обладающей способностью убивать клетку-мишень, экспрессирующую BCMA, а также к композиции, содержащей вышеуказанную клетку. Изобретение эффективно для лечения рака. 11 н. и 3 з.п. ф-лы, 13 ил., 2 табл., 10 пр.

КОМПОЗИЦИИ И СПОСОБЫ ДЛЯ ИЗБИРАТЕЛЬНОЙ ЭКСПРЕССИИ БЕЛКА

Изобретение относится к области биотехнологии, конкретно к получению слитых белков, и может быть использовано в медицине для лечения рака в присутствии стабилизирующего соединения. Рекомбинантным путем получают слитые белки, содержащие домен условной экспрессии, домен, содержащий интересующий белок, и расщепляемый протеазой домен, разделяющий эти два домена. Изобретение позволяет получить слитые белки, отличающиеся контролируемой экспрессией в зависимости от присутствия стабилизирующего соединения в среде. 9 н. и 59 з.п. ф-лы, 47 ил., 24 табл., 29 пр.

УЛУЧШЕННЫЕ ИММУННЫЕ КЛЕТКИ С ДВОЙНОЙ кшРНК И КОМПОЗИЦИИ, СОДЕРЖАЩИЕ ИХ

Изобретение относится к области биотехнологии, в частности к вектору экспресcии, содержащему последовательность оснований, кодирующую два типа коротких шпилечных РНК (кшРНК), которые ингибируют экспрессию генов PD-1 и TIGIT, ослабляющих функцию Т-клеток, и последовательность оснований, кодирующую химерный антигенный рецептор (CAR) или моноклональный Т-клеточный рецептор (mTCR), а также к содержащей его Т-клетке. Также раскрыта фармацевтическая композиция, содержащая указанную Т-клетку. Изобретение эффективно для лечения злокачественного новообразования. 9 н. и 105 з.п. ф-лы, 24 ил., 1 табл., 11 пр.

КОМПОЗИЦИИ И СПОСОБЫ ИММУНОТЕРАПИИ

Настоящее изобретение относится к иммунологии. Предложена Т-клетка для снижения опухолевой нагрузки и/или лечения неоплазии, содержащая T-клеточный рецептор (TCR) или химерный рецептор антигена (CAR), который связывается с антигеном В-клеточного лейкоза, и ингибирующий химерный рецептор антигена (iCAR), который содержит домен внутриклеточной передачи сигнала CTLA-4 или PD-1. Кроме того, описано применение такой Т-клетки для снижения опухолевой нагрузки и/или размера опухоли и фармацевтическая композиция. Также представлены вектор, композиция и способ получения Т-клетки. Использование iCAR позволяет снизить цитотоксичность Т-клетки в отношении клеток ненеопластической ткани. 8 н. и 10 з.п. ф-лы, 23 ил., 1 пр.

КОМПОЗИЦИИ И СПОСОБЫ ДЛЯ ИММУНОТЕРАПИИ

Настоящее изобретение относится к иммунологии. Предложена Т-клетка, содержащая химерный рецептор антигена (CAR) и химерный костимулирующий рецептор (CCR), а также способ получения такой клетки. Описаны способы индукции гибели клеток опухоли, лечения и предотвращения неоплазмы, фармацевтическая композиция и набор для иммунотерапии. Связывание CCR с антигеном обеспечивает доставку костимулирующего сигнала к Т-клетке, что обеспечивает более высокую степень цитолитической активности. 7 н. и 44 з.п. ф-лы, 6 ил., 1 табл., 1 пр.

СКОНСТРУИРОВАННЫЕ ВЫСОКОАФФИННЫЕ T-КЛЕТОЧНЫЕ РЕЦЕПТОРЫ ЧЕЛОВЕКА

Предложенная группа изобретений относится к иммунологии. Предложен модифицированный T-клеточный рецептор (TCR) и его антигенсвязывающий фрагмент, способные связывать сурвивин. Кроме того, представлены композиции, нацеленные на клетки рака, и способ лечения субъекта, имеющего рак. Данная группа изобретений может найти дальнейшее применение в терапии рака. 6 н. и 5 з.п. ф-лы, 5 табл., 9 пр., 9 ил.

ЛЕЧЕНИЕ РАКА С ПОМОЩЬЮ ГУМАНИЗИРОВАННОГО АНТИ-CD19 ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА

Настоящее изобретение относится к области иммунологии. Предложены выделенная молекула нуклеиновой кислоты, кодирующая анти-CD19 химерный антигенный рецептор, выделенная молекула анти-CD19 химерный антигенный рецептор, а также гуманизированный анти-CD19-связывающий домен. Кроме того, рассмотрен вектор, клетки, способ получения клетки, способ получения популяции клеток, способ создания противоопухолевого иммунитета и способ лечения. Также описаны выделенные молекулы нуклеиновой кислоты, кодирующие анти-CD19 CAR. Данное изобретение может найти дальнейшее применение в терапии различных пролиферативных заболеваний, ассоциированных с экспрессией CD19, в частности рака. 15 н. и 68 з.п. ф-лы, 12 ил., 6 табл., 6 пр.

УЛУЧШЕННЫЕ АНТИГЕНСВЯЗЫВАЮЩИЕ РЕЦЕПТОРЫ

Изобретение относится к области биотехнологии. Предложены антигенсвязывающие рецепторы, содержащие заякоренный трансмембранный домен и внеклеточный домен, включающий антигенсвязывающий фрагмент. Антигенсвязывающие рецепторы специфически связываются с мутированными Fc-доменами, но не связываются с немутированными исходными Fc-доменами. Изобретение обеспечивает специфическую активацию трансдуцированных Т-клеток, экспрессирующих указанные антигенсвязывающие рецепторы, в присутствии антитела IgG с мутированным Fc-доменом для эффективного лизиса опухолевых клеток-мишеней. 4 н. и 27 з.п. ф-лы, 35 ил., 12 табл., 9 пр.

CD3-СПЕЦИФИЧЕСКИЕ СВЯЗЫВАЮЩИЕ МОЛЕКУЛЫ

Группа изобретений относится к биотехнологии. Раскрыты: специфическая связывающая молекула, которая связывается с CD3, бифункциональная связывающая молекула, способная связываться с CD3 и клеткой-мишенью, и способы их получения, фармацевтические композиции для лечения рака и инфекционного заболевания, нуклеиновые кислоты, кодирующие специфическую и бифункциональную связывающие молекулы, экспрессионный вектор, клетки-хозяина для получения специфической и бифункциональной связывающих молекул. Также раскрыты способы лечения рака и инфекционного заболевания. Изобретение направлено на получение связывающих молекул, которые связываются с CD3, и их использование для лечения рака и инфекционного заболевания у субъекта. 13 н. и 14 з.п. ф-лы, 4 ил., 2 табл.

МЕЧЕНЫЕ ХИМЕРНЫЕ ЭФФЕКТОРНЫЕ МОЛЕКУЛЫ И ИХ РЕЦЕПТОРЫ

Группа изобретений относится к гибридным белкам, содержащим кассету с Strep-меткой и к меченым химерным эффекторным молекулам, меченым химерным молекулам антигенных рецепторов, рекомбинантным клеткам-хозяевам, продуцирующим такие гибридные белки. Одноцепочечный гибридный белок для активации и стимулирования пролиферации Т-клеток содержит трансмембранный домен, расположенный между внеклеточным компонентом и внутриклеточным компонентом, содержащим эффекторный домен. Внеклеточный компонент содержит домен связывания, который специфически связывает мишень, множество меток и соединительную область, содержащую шарнир. Множество меток содержит от двух до пяти меток и по меньшей мере две из множества меток содержат Strep-метку. Рекомбинантные клетки-хозяева, продуцирующие такие гибридные белки, можно идентифицировать, отделить, отсортировать, вызвать пролиферацию, отследить, устранить и/или использовать в качестве терапевтического средства в адоптивной иммунотерапии. Изобретения позволяют в значительной ...

ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР (CAR) ПРОТИВ CD123 ДЛЯ ИСПОЛЬЗОВАНИЯ В ЛЕЧЕНИИ ЗЛОКАЧЕСТВЕННЫХ ОПУХОЛЕЙ

Настоящее изобретение относится к иммунологии. Предложены CD123-связывающий домен, содержащий его химерный антигенный рецептор (CAR) и кодирующая рецептор нуклеиновая кислота. Также рассмотрены вектор экспрессии, экспрессирующая CAR клетка и популяция таких клеток, способы их получения. Кроме того, описаны способы обеспечения противоопухолевого иммунитета, лечения млекопитающего, профилактики CD19-отрицательного рецидива, уменьшения или истощения экспрессирующих CD123 CAR клеток после терапии CAR, а также способ воздействия на индивидуум клетками по настоящему изобретению с целью подготовки к трансплантации. Данное изобретение может найти дальнейшее применение в терапии CD123-ассоциированных заболеваний. 14 н. и 87 з.п. ф-лы, 75 ил., 17 табл., 2 пр.

БИБЛИОТЕКИ TCR

Настоящее изобретение относится к иммунологии. Предложены библиотеки частиц, характеризующиеся дисплеем множества различных рецепторов Т-клеток (TCR), причем множество TCR по существу состоит из TCR, включающих вариабельный домен альфа-цепи из естественного репертуара TRAV12-2 или TRAV21 и вариабельный домен бета-цепи из естественного репертуара TRBV6. Кроме того, рассмотрены применение библиотек и способы получения TCR, а также способы получения библиотек частиц. Данное изобретение может найти дальнейшее применение в скрининге TCR, подходящих для применения в иммунотерапевтических целях. 7 н. и 17 з.п. ф-лы, 8 ил., 11 пр.

ОПУХОЛЕСПЕЦИФИЧНОЕ АНТИТЕЛО ПРОТИВ EGFR И ЕГО ПРИМЕНЕНИЕ

Изобретение относится к области биотехнологии. Описана группа изобретений, включающая антитело, специфически распознающее экспрессируемый опухолевыми клетками EGFRvIII или сверхэкспрессируемый EGFR, нуклеиновую кислоту, кодирующую вышеуказанное антитело, вектор экспрессии, клетку-хозяин, применение антитела для получения направленно действующего лекарственного средства, специфически направленного на опухолевые клетки, применение антитела для получения конъюгата антитела с лекарственным средством, специфически направленного на опухолевые клетки, применение антитела для получения многофункционального антитела, специфически направленного на опухолевые клетки, применение антитела для получения средства для диагностики опухолей, применение антитела для получения иммунной клетки, модифицированной химерным антигенным рецептором, иммуноконъюгат (варианты), применение иммуноконъюгата для получения средства против опухолей, применение иммуноконъюгата для получения средства для диагностики опухолей ...

ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР

Настоящее изобретение относится к иммунологии. Предложен химерный антигенный рецептор (CAR), который содержит дисиалоганглиозид (GD2)-связывающий домен. Кроме того, представлены нуклеиновая кислота, кодирующая CAR по изобретению; вектор экспрессии; Т-клетки и способ получения Т-клетки. Также описаны фармацевтическая композиция, способ лечения злокачественной опухоли и применение T-клетки в получении лекарственного средства для лечения злокачественной опухоли. Предложенный CAR обеспечивает увеличенное продуцирование INF-γ, пролиферацию CAR-T-клеток и уничтожение клеток нейробластомы по сравнению с CAR на основе антитела 14g2a. Данное изобретение может найти дальнейшее применение в терапии. 9 н. и 17 з.п. ф-лы, 15 ил., 10 пр.

ИММУНОМОДУЛИРУЮЩИЕ СЛИТЫЕ БЕЛКИ И ПУТИ ИХ ПРИМЕНЕНИЯ

Изобретение относится к области биотехнологии, конкретно к слитому белку, связывающемуся с CD47 для передачи костимулирующего сигнала CD28 Т-клетке, и может быть использовано в медицине. Слитый белок, состоящий из CD47-связывающей части SIRPα, трансмембранной части CD28 и сигнального домена костимулирующей молекулы CD28, может быть использован для создания Т-клеток для эффективной иммунотерапии рака, экспрессирующего CD47. 9 н. и 42 з.п. ф-лы, 13 ил., 13 пр.

ХИМЕРНЫЕ АНТИГЕННЫЕ РЕЦЕПТОРЫ К КАППА-АНТИГЕНУ МИЕЛОМЫ И ВАРИАНТЫ ИХ ПРИМЕНЕНИЯ

Настоящее изобретение относится к области иммунологии. Предложены химерный антигенный рецептор к каппа-антигену миеломы (КМА), генетически модифицированная Т-клетка, способ получения генетически модифицированной Т-клетки, применение генетически модифицированной Т-клетки. Данное изобретение может найти дальнейшее применение в терапии КМА-экспрессирующих злокачественных новообразований. 4 н. и 16 з.п. ф-лы, 23 ил., 5 пр.

СПОСОБ И КОМПОЗИЦИИ ДЛЯ КЛЕТОЧНОЙ ИММУНОТЕРАПИИ

Группа изобретений относится к медицине, а именно к онкологии, и может быть использована для адаптивной клеточной иммунотерапии. Композиция по изобретению содержит T-лимфоциты CD4и T-лимфоциты CD8, модифицированные химерным рецептором антигена. Применение композиции по изобретению предназначено для изготовления лекарственного средства для лечения рака. Способ изготовления композиции для адаптивной клеточной иммунотерапии включает стадию размножения in vitro, по отдельности, популяции T-лимфоцитов CD8, обогащенной центральными T-клетками памяти, и популяции T-лимфоцитов CD4и стадию модификации клеток. Использование изобретений позволяет усилить иммунный ответ за счет синергического действия модифицированных клеток. 3 н. и 16 з.п. ф-лы, 13 ил., 6 пр.

НОВЫЕ КОНСТРУКЦИИ ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА, СОДЕРЖАЩИЕ ДОМЕНЫ TNFR2

Изобретение относится к области биотехнологии, в частности к химерному антигенному рецептору (CAR) с более низкой тонической передачей сигналов при экспрессии в иммунных клетках по сравнению с иммунными клетками, экспрессирующими CAR без внутриклеточного костимулирующего сигнального домена TNFR2, а также нуклеиновой кислоте, его кодирующей. Также раскрыты иммунная клетка, экспрессирующая вышеуказанный CAR, а также популяция, ее содержащая. Изобретение эффективно для лечения заболевания или расстройства у человеческого субъекта, где заболевание или расстройство выбрано из группы, состоящей из воспалительного заболевания, аутоиммунного заболевания, аллергического заболевания, состояния после трансплантации органов, рака и инфекционного заболевания. 4 н. и 13 з.п. ф-лы, 15 ил., 13 табл., 5 пр.

ХИМЕРНЫЕ АНТИГЕННЫЕ РЕЦЕПТОРЫ, НАЦЕЛЕННЫЕ НА ПОДОБНЫЙ FC-РЕЦЕПТОРУ БЕЛОК 5, И ИХ ПРИМЕНЕНИЕ

Изобретение относится к области биотехнологии, в частности к химерному антигенному рецептору (CAR), который связывается с подобным Fc-рецептору белком 5 (FcRL5), а также к содержащим его композиции и набору. Также раскрыта молекула нуклеиновой кислоты, кодирующая вышеуказанный CAR, а также содержащие ее клетка и вектор. Изобретение эффективно для лечения опухоли, экспрессирующей FcRL5. 16 н. и 76 з.п. ф-лы, 27 ил., 240 табл., 10 пр.

КЛЕТКИ, ЭКСПРЕССИРУЮЩИЕ ХИМЕРНЫЕ АКТИВИРУЮЩИЕ РЕЦЕПТОРЫ И ХИМЕРНЫЕ СТИМУЛИРУЮЩИЕ РЕЦЕПТОРЫ, И ИХ ПРИМЕНЕНИЕ

Группа изобретений относится к биотехнологии. Представлены: Т–клетки, содержащие конструкцию химерное антитело – T–клеточный рецептор и конструкцию химерного сигнального рецептора. Химерное антитело – T–клеточный рецептор содержит антигенсвязывающий модуль, который специфически связывается с целевым антигеном, и модуль Т–клеточного рецептора, способный рекрутировать по меньшей мере одну ТКР–ассоциированную сигнальную молекулу, а химерный сигнальный рецептор содержит лигандсвязывающий домен, который специфически связывается с целевым лигандом, и костимулирующий сигнальный домен, способный обеспечивать стимулирующий сигнал иммунной клетке. Также предложены: нуклеиновая кислота, экспрессионный вектор, фармацевтическая композиция, способ уничтожения целевой клетки, способ лечения ракового заболевания у нуждающегося в этом индивида и способ обеспечения костимулирующего сигнала Т-клетке. Изобретение позволяет лечить раковое заболевания у нуждающегося в этом индивида, где раковое заболевание связано ...

ЛЕЧЕНИЕ РАКА С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО АНТИГЕНСПЕЦИФИЧЕСКОГО РЕЦЕПТОРА НА ОСНОВЕ ГУМАНИЗИРОВАННОГО АНТИТЕЛА ПРОТИВ EGFRvIII

Настоящее изобретение относится к иммунологии. Предложен связывающий домен против EGFRvIII, содержащий его химерный антигенный рецептор, кодирующие нуклеиновые кислоты, вектор, клетка, а также применения указанных изобретений в производстве лекарственного средства, способы создания клетки и получения популяции клеток, способ обеспечения иммунитета, способ лечения. Данное изобретение может найти дальнейшее применение в терапии с использованием адоптивного переноса клеток. 22 н. и 81 з.п. ф-лы, 18 ил., 9 пр., 2 табл.

РЕЖИМ ДОЗИРОВАНИЯ ДЛЯ ГИБРИДНОГО БЕЛКА GP100-СПЕЦИФИЧНЫЙ ПЕРЕНАПРАВЛЯЮЩИЙ TCR-АНТИ-CD3 SCFV

Изобретение относится к области биотехнологии. Предложено применение перенаправляющего Т-клетки биспецифичного терапевтического средства для лечения gp100-положительного рака у пациента. Терапевтическое средство содержит нацеливающий фрагмент, который представляет собой рецептор Т-клеток и связывает комплекс YLEPGPVTA-HLA-A2, слитый с перенаправляющим Т-клетки фрагментом, представляющим собой антитело к CD3. Режим дозирования перенаправляющего Т-клетки биспецифичного терапевтического средства обеспечивает возможность лечения gp100-положительного рака с улучшенной переносимостью у пациента. 2 н. и 8 з.п. ф-лы, 10 ил., 2 табл., 2 пр.

КОМПОЗИЦИИ АНТИТЕЛ К ROR1 И СООТВЕТСТВУЮЩИЕ СПОСОБЫ

Группа изобретений относится к иммунологии и терапии заболеваний или состояний, ассоциированных с повышенной экспрессией человеческого ROR1. Предложены антитела, которые специфически распознают человеческий ROR1, конъюгаты антитело-лекарственное средство (ADCs), химерные антигенные рецепторы (CARs), композиции на их основе и их применения. Антитело или антигенсвязывающий фрагмент антитела включает последовательности CDRs тяжелой и легкой цепей, показанные в (1) SEQ ID NO:27-29 и SEQ ID NO:66-68; (2) SEQ ID NO:30-32 и SEQ ID NO:69-71; (3) SEQ ID NO:33-35 и SEQ ID NO:72-74; (4) SEQ ID NO:36-38 и SEQ ID NO:75-77; (5) SEQ ID NO:39-41 и SEQ ID NO:78-80; (6) SEQ ID NO:42-44 и SEQ ID NO:81-83; (7) SEQ ID NO:45-47 и SEQ ID NO:84-86; (8) SEQ ID NO:48-50 и SEQ ID NO:87-89; (9) SEQ ID NO:51-53 и SEQ ID NO:90-92; (10) SEQ ID NO:54-56 и SEQ ID NO:93-95; (11) SEQ ID NO:57-59 и SEQ ID NO:96-98; (12) SEQ ID NO:60-62 и SEQ ID NO:99-101; или (13) SEQ ID NO:63-65 и SEQ ID NO:102-104. Предложенные анти-ROR1 ...

ХИМЕРНЫЙ АНТИГЕННЫЙ РЕЦЕПТОР (CAR) С АНТИГЕНСВЯЗЫВАЮЩИМИ ДОМЕНАМИ К КОНСТАНТНОЙ ОБЛАСТИ β Т-КЛЕТОЧНОГО РЕЦЕПТОРА

Настоящее изобретение относится к области иммунологии. Предложены применение цитолитической Т-клетки, цитолитическая Т-клетка, CAR. Также рассмотрены молекула нуклеиновой кислоты, вектор экспрессии, способ получения клетки, способ лечения Т-клеточной лимфомы или лейкемии. Данное изобретение может найти дальнейшее применение в терапии онкологических заболеваний, связанных со злокачественными Т-клетками. 7 н. и 11 з.п. ф-лы, 29 ил., 6 табл., 13 пр.

ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ОБЛАДАЮЩАЯ ПРОТИВООПУХОЛЕВЫМ ЭФФЕКТОМ, И СПОСОБ СНИЖЕНИЯ ИНГИБИРУЮЩЕГО ЭФФЕКТА PD-L1 НА Т-КЛЕТКИ ЧЕЛОВЕКА

Группа изобретений относится к медицине и касается фармацевтической композиции, обладающей противоопухолевым эффектом, содержащей эффективное количество популяций Т-клеток человека, где Т-клетки человека включают изолированную нуклеотидную последовательность, содержащую нуклеотидную последовательность, кодирующую модифицированный белок запрограммированной смерти клетки 1 (PD-1) и нуклеотидную последовательность, кодирующую химерный антигенный рецептор (CAR), где модифицированный PD-1 и CAR экспрессируются в виде генных продуктов, которые являются отдельными полипептидами, и где модифицированный PD-1 является доминантно-негативным PD-1. Группа изобретений также касается способа снижения ингибирующего эффекта PD-L1 на Т-клетки человека, включающего введение первой нуклеотидной последовательности и второй нуклеотидной последовательности в Т-клетки человека. Где первая нуклеотидная последовательность кодирует модифицированный PD-1, который является доминантно-негативным PD-1, и вторая нуклеотидная ...

Терапевтические средства

Настоящее изобретение относится к области иммунологии. Предложена иммунореактивная клетка для лечения рака, экспрессирующая химерный антигенный рецептор второго поколения и химерный костимулирующий рецептор. Кроме того, рассмотрен способ получения иммунореактивной клетки, комбинация нуклеиновых кислот, вектор, комбинация векторов, способ стимуляции иммунного ответа. Данное изобретение может найти дальнейшее применение в терапии различных видов рака. 6 н. и 14 з.п. ф-лы, 25 ил., 4 пр.

СПОСОБЫ ОПРЕДЕЛЕНИЯ ДОЗИРОВКИ CART-КЛЕТОК

НОВЫЕ ПЕПТИДЫ И КОМБИНАЦИИ ПЕПТИДОВ ДЛЯ ПРИМЕНЕНИЯ В ИММУНОТЕРАПИИ РАКА ЛЕГКИХ, В ТОМ ЧИСЛЕ НЕМЕЛКОКЛЕТОЧНОГО РАКА ЛЕГКИХ (НМРЛ) И ДРУГИХ ВИДОВ РАКА

ВАРИАНТЫ, КОМПОЗИЦИИ И МЕТОДЫ ПРИМЕНЕНИЯ ХОМИНГ-ЭНДОНУКЛЕАЗЫ PD-1

ЭПИТОПНЫЕ ПЕПТИДЫ HIG2 И URLC10 И СОДЕРЖАНИЕ ИХ ВАКЦИНЫ

... 1. Фармацевтическое средство, где средство содержит один или несколько пептидов, способных индуцировать цитотоксический T-лимфоцит (ЦТЛ), где пептид содержит аминокислотную последовательность, которая выбрана из группы, состоящей из: ! (a) SEQ ID NO:1, и 2; и ! (b) SEQ ID NO:1, и 2, где 1, 2 или несколько аминокислот замещены, вставлены, удалены и/или добавлены, ! или один или несколько полинуклеотидов, кодирующих такой пептид, в сочетании с фармакологически приемлемым носителем, и составлено с целью, которая выбрана из группы, состоящей из: ! (i) лечение рака у пациента, у которого HLA-A антиген является HLA-A0206, ! (ii) профилактика рака у пациента, у которого HLA-A антиген является HLA-A0206, ! (iii) предупреждение послеоперационного рецидива рака у пациента, у которого HLA-A антиген является HLA-A0206, и ! (iv) их сочетания. ! 2. Фармацевтическое средство по п.1, где указанный рак выбран из группы, состоящей из рака мочевого пузыря, рака шейки матки, холангиоцеллюлярной карциномы, ...

ЛЕЧЕНИЕ РАКА С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА CLL-1

Т-КЛЕТОЧНЫЕ РЕЦЕПТОРЫ

Изобретение относится к области биотехнологии, конкретно к Т-клеточным рецепторам (TCR), которые связываются с комплексом HLA-A*02 c раковым антигеном MAGE A4 GVYDGREHTV (SEQ ID NO: 1), и может быть использовано в медицине. Полученные TCR могут входить в состав гибридной молекулы TCR-анти-CD3, содержащей TCR и антитело против CD3, для перенаправления Т-клеток на клетки, презентирующие антиген MAGE-A4, и могут быть использованы для эффективной терапии MAGE A4 экспрессирующих опухолей. 19 н. и 26 з.п. ф-лы, 11 ил., 12 табл., 7 пр.

ДОСТАВКА ТЕРАПЕВТИЧЕСКИХ ПОЛИПЕПТИДОВ ПОСРЕДСТВОМ ПСЕВДОТИПИРОВАННЫХ ОНКОЛОГИЧЕСКИХ ВИРУСОВ

СПОСОБЫ, НАБОРЫ И УСТРОЙСТВО ДЛЯ РАЗМНОЖЕНИЯ ПОПУЛЯЦИИ КЛЕТОК

СПОСОБ МОДУЛЯЦИИ АКТИВНОСТИ CAR-ИНДУЦИРОВАННЫХ ИММУННЫХ КЛЕТОК

ИНСЕРЦИЯ ТАРГЕТНОГО ГЕНА ДЛЯ УЛУЧШЕННОЙ КЛЕТОЧНОЙ ИММУНОТЕРАПИИ

ИММУННЫЕ ЭФФЕКТОРНЫЕ КЛЕТКИ С ОТРЕДАКТИРОВАННЫМ ГЕНОМОМ

ЛЕЧЕНИЕ ЗЛОКАЧЕСТВЕННОЙ ОПУХОЛИ С ИСПОЛЬЗОВАНИЕМ ХИМЕРНОГО РЕЦЕПТОРА АНТИГЕНА ПРОТИВ CD19

МОДИФИКАЦИЯ Т-КЛЕТОК

КОМПОЗИЦИИ, ИЗДЕЛИЯ И СПОСОБЫ, СВЯЗАННЫЕ С ДОЗИРОВАНИЕМ В КЛЕТОЧНОЙ ТЕРАПИИ

СКОНСТРУИРОВАННЫЕ УНИВЕРСАЛЬНЫЕ ИММУННЫЕ КЛЕТКИ С АНТИ-CD22 ХИМЕРНЫМ АНТИГЕННЫМ РЕЦЕПТОРОМ

ХИМЕРНЫЕ РЕЦЕПТОРЫ АНТИГЕНА, НАЦЕЛЕННЫЕ НА PSCA

ПОЛИПЕПТИДЫ ТРАНСПОЗАЗЫ И ИХ ПРИМЕНЕНИЕ

ЛЕЧЕНИЕ РАКА С ПОМОЩЬЮ ГУМАНИЗИРОВАННОГО АНТИ-CD19 ХИМЕРНОГО АНТИГЕННОГО РЕЦЕПТОРА

СКОНСТРУИРОВАННЫЕ ВЫСОКОАФФИННЫЕ T-КЛЕТОЧНЫЕ РЕЦЕПТОРЫ ЧЕЛОВЕКА

МАт-НАПРАВЛЯЕМЫЕ ХИМЕРНЫЕ АНТИГЕННЫЕ РЕЦЕПТОРНЫЕ СИСТЕМЫ ДЛЯ СОРТИРОВКИ/ИСТОЩЕНИЯ СКОНСТРУИРОВАННЫХ ИММУННЫХ КЛЕТОК

СКОНСТРУИРОВАННЫЕ ИММУННЫЕ КЛЕТКИ С НОКАУТОМ РЕЦЕПТОРА Т-КЛЕТОК, СНАБЖЕННЫЕ ХИМЕРНЫМИ АНТИГЕННЫМИ РЕЦЕПТОРАМИ, СВЯЗЫВАЮЩИМИСЯ С CD123, ДЛЯ ЛЕЧЕНИЯ РЕЦЕДИВИРУЮЩЕГО/УСТОЙЧИВОГО ОСТРОГО МИЕЛОИДНОГО ЛЕЙКОЗА ИЛИ НОВООБРАЗОВАНИЯ ИЗ БЛАСТНЫХ ПЛАЗМОЦИТОИДНЫХ ДЕНДРИТНЫХ КЛЕТОК

ДОСТАВКА ТЕРАПЕВТИЧЕСКИХ ПОЛИПЕПТИДОВ ПОСРЕДСТВОМ ПСЕВДОТИПИРОВАННЫХ ОНКОЛИТИЧЕСКИХ ВИРУСОВ

АНТИГЕНСВЯЗЫВАЮЩИЙ БЕЛОК, РАСПОЗНАЮЩИЙ ПРОИСХОДЯЩИЙ ИЗ MAGE-A4-ПЕПТИД

ВВЕДЕНИЕ СКОНСТРУИРОВАННЫХ Т-КЛЕТОК ДЛЯ ЛЕЧЕНИЯ РАКА ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ

ХИМЕРНЫЕ АНТИГЕННЫЕ РЕЦЕПТОРЫ, СПЕЦИФИЧНЫЕ В ОТНОШЕНИИ РЕЦЕПТОРА ТИМУСНОГО СТРОМАЛЬНОГО ЛИМФОПОЭТИНА, И СПОСОБЫ ИХ ПРИМЕНЕНИЯ

СОЧЕТАНИЕ КЛЕТОЧНОЙ ТЕРАПИИ И ИММУНОМОДУЛЯТОРНОГО СОЕДИНЕНИЯ

Т-КЛЕТОЧНЫЕ РЕЦЕПТОРЫ

НАЦЕЛИВАНИЕ НА КЛЕТКИ, ОПОСРЕДУЕМОЕ ХИМЕРНЫМ АНТИГЕННЫМ РЕЦЕПТОРОМ

КОМБИНИРОВАННАЯ ТЕРАПИЯ ДЛЯ ЛЕЧЕНИЯ СВЯЗАННЫХ С BCMA РАКОВЫХ ЗАБОЛЕВАНИЙ И АУТОИММУННЫХ РАССТРОЙСТВ

БИОСЕНСОРНАЯ СИСТЕМА ДЛЯ БЫСТРОГО ОБНАРУЖЕНИЯ ОПРЕДЕЛЯЕМЫХ КОМПОНЕНТОВ

КОМПОЗИЦИИ АНТИТЕЛ К ВИЧ И СПОСОБЫ ИХ ПРИМЕНЕНИЯ

VERFAHREN UND ZUSAMMENSETZUNG FÜR DIE MODULATION DER WIRTSIMMUNANTWORT AUF ALLERGENE

Detection of CD4+ T lymphocytes

Nucleic Acid Construct

T cell receptors

Novel peptides and combination of peptides for use in immunotherapy against prostate cancer and other cancers

T Cell receptor

Diabetes t cell receptors

Viral methods of T cell therapy

Methods of producing a population of genetically modified cells using viral or non-viral vectors. Disclosed are also modified viruses for producing a population of genetically modified cells and/or for the treatment of cancer.

Anti-placenta-chondroitin-sulfate chimeric antigen receptor and application thereof

The present invention provides an anti-placenta chondroitin sulfate (pl-CS) chimeric antigen receptor and application thereof. The chimeric antigen receptor mainly comprises anti-pl-CS antigen recognition region, a hinge region, a transmembrane region and intracellular region, wherein the anti-pl-CS antigen recognition region is any one of a plasmodium protein VAR2CSA, a part of peptide segment of plasmodium protein VAR2CSA or a pl-CS antibody; and the part of peptide segment of the plasmodium protein VAR2CSA is a peptide segment with the number of amino acid greater than 500 in the plasmodium protein VAR2CSA.

T Cell Receptors

Antigen-binding molecule format

Chimeric protein

Gamma delta T cells and uses thereof

Peptides

Modified cells and methods of therapy

Immunological method

Engineered regulatory t cell

Molecule

Cell

Therapeutic agents

Cell

Modified T cells

Compositions and methods for identifying enzyme and transport protein inhibitors

The invention is directed to compositions, e.g., cell-based and multiplexed platforms, to screen for small molecule drugs that inhibit enzymes such as proteases, e.g., viral proteases, e.g., HIV proteases; and methods for making and using these compositions. The invention provides compositions and methods for identifying compositions, e.g., drug molecules, that can inhibit proteases, e.g., viral proteases such as HIV proteases. In alternative embodiments, the invention provides cell-based platforms or assays to screen for compositions, e.g., small molecules or drugs, that inhibit or modify the activity of enzymes such as calcium-dependent protein convertases involved in HIV envelope protein processing, including cleavage of the HIV gp160 envelope precursor, resulting in gp120 and gp41 envelope products. In one embodiment, the invention provides a cell-based or multiplexed platform for monitoring the activity of enzymes, e.g., proteases such as viral proteases.

Molecular complexes which modify immune responses

Extracellular domains of transmembrane heterodimeric proteins, particularly T cell receptor and major histocompatibility complex proteins, can be covalently linked to the heavy and light chains of immunoglobulin molecules to provide soluble multivalent molecular complexes with high affinity for their cognate ligands. The molecular complexes can be used, inter alia, to detect and regulate antigen-specific T cells and as therapeutic agents for treating disorders involving immune system regulation, such as allergies, autoimmune diseases, tumors, infections, and transplant rejection.

Fusion proteins comprising cd4 minimal modules and methods of use thereof

Fusion proteins comprising CD4 minimal modules that bind to HIV Env polypeptides in a non-CD4 backbone are described. Also described are complexes of these fusion proteins with Env as well as methods of diagnosis, treatment and prevention using the polynucleotides and polypeptides are also provided.

Hiv tat-cd4 hybrid molecules and methods of use thereof

Hybrid molecules comprising CD4 minimal modules or mimetics that bind to HIV Env polypeptides in combination with one or more HIV Tat polypeptides are described. Also described are complexes of these hybrid molecules with Env as well as methods of diagnosis, treatment and prevention using the polynucleotides and polypeptides.

Fusion molecules and il-15 variants

The instant invention provides soluble fusion protein complexes and IL-15 variants that have therapeutic and diagnostic use, and methods for making the such proteins. The instant invention additionally provides methods of stimulating or suppressing immune responses in a mammal using the fusion protein complexes and IL-15 variants of the invention.

Methods for engineering t-cell receptors

The present invention provides a method for engineering a T-cell receptor domain polypeptide comprising at least one modification in a structural loop region of the T-cell receptor domain polypeptide and determining the binding of the T-cell receptor domain polypeptide to an epitope of an antigen, wherein the unmodified T-cell receptor domain polypeptide does not significantly bind to said epitope. The present invention also covers modified T cell receptor domain polypeptides, their use and libraries containing the modified T cell receptor domain polypeptides.

High affinity ny-eso t cell receptors

The present invention provides T cell receptors (TCRs) having the property of binding to SLLMWITQC-HLA-A*0201, the SLLMWITQC SEQ ID NO:126 peptide being derived from the NY-ESO-1 protein which is expressed by a range of tumour cells. The TCRs have a K D for the said peptide-HLA complex of less than or equal to 1 μM and/or have an off-rate (k off ) of 1×10 −3 S −1 or slower.

Methods of cell culture for adoptive cell therapy

An improved method of culturing cells for cell therapy applications that includes growing desired cells in the presence of antigen-presenting cells and/or feeder cells and with medium volume to surface area ratio of up to 1 ml/cm 2 if the growth surface is not comprised of gas permeable material and up to 2 ml/cm 2 if the growth surface is comprised of gas permeable material. The desired cells are at a surface density of less than 0.5×10 6 cells/cm 2 at the onset of a production cycle, and the surface density of the desired cells plus the surface density of the antigen presenting cells and/or feeder cells are at least about 1.25×10 5 cells/cm 2 .

BIVALENT MOLECULES FOR HIV ENTRY INHIBITION

The present invention relates to a new class of virus fusion inhibitors or virus entry inhibitors. More specifically the present invention relates to bivalent molecules that are pre-fusion inhibitors of viruses that makes use of the type (1) fusion mechanism belonging to the groups consisting of Othomyxoviridae, Paramyxoviridae, Retroviridae, Filoviridae and Coronaviridae, in particular HIV. The bivalent molecules of the present invention are molecules that comprise a first part capable of mimicking the function of a mammalian cell receptor, and a second part capable of binding to a virus, preferably HIV, resulting in the neutralization of the virus which is thus rendered harmless. Further, the present invention relates to compositions comprising the pre-fusion inhibitors, as well as to methods for obtaining the pre-fusion inhibitors and the use of the pre-fusion inhibitors. 1161-. (canceled)162. A pre-fusion inhibitor molecule comprising:i) a first part that comprises or consists of a first virus binding moiety that binds to a first viral protein; and wherein said first part comprises or consists of an amino acid sequence of a mammalian membrane receptor or a fragment, mimic or functional homologue thereof;', 'or wherein said first or second part is an antibody or an antigen-binding fragment., 'ii) a second part that comprises or consists of a second virus binding moiety that binds to a second viral protein;'}163. The molecule according to claim 162 , wherein said fragment is at least 75 amino acids long; and wherein said functional homologue is at least 40 percent homologous with said mammalian membrane receptor.164. The molecule according to claim 162 , wherein said first viral protein is HIV gp120 claim 162 , said second viral protein is HIV gp41 claim 162 , andsaid first part is mammalian soluble CD4 (sCD4) or a fragment, or functional homologue thereof, oran amino acid sequence at least 80% identical to soluble CD4 (sCD4) or a fragment, or functional homologue ...

ANTI-MART-1 T CELL RECEPTORS AND RELATED MATERIALS AND METHODS OF USE

The invention provides a chimeric T cell receptor (TCR) comprising a variable region of a human TCR and a constant region comprising at least an extracellular domain of a constant region of a non-human TCR, as well as functional variants thereof. The invention also provides polypeptides and proteins related to the inventive TCRs, as well as nucleic acids encoding the TCRs, polypeptides, or proteins, recombinant expression vectors, and host cells. Further provided are pharmaceutical compositions related to the inventive TCRs and methods of preventing or treating a disease, e.g., an infectious disease, cancer, in a host, methods of detecting a diseased cell in a host, and methods of improving the biological activity of a TCR. 118-. (canceled)19. A chimeric TCR comprising a variable region of a human TCR and a constant region comprising at least an extracellular domain of a constant region of a non-human TCR , or a functional variant thereof , wherein the chimeric TCR has antigenic specificity for a cancer antigen selected from the group consisting of MART-1 , wherein the functional variant has at least about 75% sequence identity to the chimeric TCR and specifically binds to the antigen for which the chimeric TCR has antigenic specificity.20. The chimeric TCR of claim 19 , wherein the non-human TCR is a murine TCR.21. The chimeric TCR of claim 20 , wherein the extracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 3.22. The chimeric TCR of claim 21 , wherein the constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 4 to 6.23. The chimeric TCR of claim 20 , wherein the functional variant comprises a constant region in which a portion of the constant region is derived from a murine constant region and another portion of the constant region is derived from a human constant region2425-. (canceled)26. The chimeric TCR of claim 20 , wherein the functional variant comprises a ...

Cells expressing modified t cell receptor

This invention provides a cell presenting at least one T cell receptor (TCR) anchored to the membrane by a trans-membrane sequence, said TCR comprising an interchain disulfide bond between extracellular constant domain residues which is not present in native TCRs.

T cell receptors and related materials and methods of use

The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a cancer antigen, e.g., a renal cell carcinoma antigen, wherein the TCR recognizes the cancer antigen in a major histocompatibility complex (MHC)-independent manner. Also provided are related polypeptides, proteins, nucleic acids, recombinant expression vectors, isolated host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions. The invention further provides a method of detecting the presence of cancer in a host and a method of treating or preventing cancer in a host using the inventive TCRs or related materials.

Method for the treatment of obesity

The present invention relates to therapeutic compositions for treating or preventing obesity and obesity-related disorders in a subject using immunotherapy to target and eliminate adipocytes.

Expansion of Interferon-Gamma-Producing T-Cells Using Glypican-3 Peptide Library

The present invention encompasses a method for expanding an antigen specific T cell from a population of cells. The method of the present invention comprises contacting a population of cells with an MHC restricted antigenic glypican-3 peptide. In some instances, the T cell is expanded using monocyte-derived dendritic cells and defined MHC restricted antigenic glypican-3 peptides. In one embodiment, high-affinity antigen-specific T-cell receptors (TCRs) can be cloned from the antigen specific T cell. 1. A method of expanding an antigen specific T cell in a population of cells , the method comprising isolating the population of cells from a human , contacting the population of cells with an MHC restricted antigenic glypican-3 peptide , thereby expanding an antigen specific T cell from the population of cells.2. The method of claim 1 , wherein the human is an HLA-A2 healthy donor.3. The method of claim 1 , wherein the T cell is specific for glypican-3.4. The method of claim 1 , wherein the MHC restricted antigenic glypican-3 peptide comprises the sequence selected from the group consisting of SEQ ID NO: 2 claim 1 , SEQ ID NO: 3 claim 1 , SEQ ID NO: 4 claim 1 , SEQ ID NO: 5 claim 1 , and SEQ ID NO: 6.5. The method of claim 1 , wherein the population of cells comprises peripheral blood mononuclear cells (PBMCs).6. An isolated antigen specific T cell generated by isolating a population of cells from a human claim 1 , contacting the population of cells with an MHC restricted antigenic glypican-3 peptide claim 1 , expanding an antigen specific T cell that is reactive to the glypican-3 peptide claim 1 , and isolating the expanded antigen specific T cell using a multimer wherein the multimer comprises the glypican-3 peptide.7. The cell of claim 6 , wherein the human is an HLA-A2 healthy donor.8. The cell of claim 6 , wherein the T cell is specific for glypican-3.9. The cell claim 6 , wherein the MHC restricted antigenic glypican-3 peptide comprises the sequence selected from ...

Chimeric receptors with 4-1bb stimulatory signaling domain

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.

ANTI-SSX-2 T CELL RECEPTORS AND RELATED MATERIALS AND METHODS OF USE

The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for synovial sarcoma X Breakpoint (SSX)-2. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are further provided by the invention. 1. An isolated or purified T cell receptor (TCR) having antigenic specificity for synovial sarcoma X Breakpoint (SSX)-2 (SEQ ID NO: 1).2. The TCR of claim 1 , wherein the TCR also recognizes any one or more of SSX-3 (SEQ ID NO: 3) claim 1 , SSX-4 (SEQ ID NO: 4) claim 1 , SSX-5 (SEQ ID NO: 5) claim 1 , SSX-9 (SEQ ID NO: 6) claim 1 , and SSX-10 (SEQ ID NO: 7).3. The TCR of claim 1 , wherein the TCR has antigenic specificity for an SSX-2 peptide comprising KASEKIFYV (SEQ ID NO: 2).4. The TCR of claim 1 , wherein the TCR recognizes any one or more of KVSEKIVYV (SEQ ID NO: 8) claim 1 , KSSEKIVYV (SEQ ID NO: 9) claim 1 , KASEKIIYV (SEQ ID NO: 10) claim 1 , KSSEKIIYV (SEQ ID NO: 11) claim 1 , and KASEKILYV (SEQ ID NO: 12).5. The TCR of claim 1 , wherein the TCR comprises amino acid sequences comprising SEQ ID NOs: 13-18.6. The TCR of claim 1 , wherein the TCR comprises SEQ ID NOs: 19 and 20.7. The TCR of claim 6 , wherein the TCR further comprises SEQ ID NOs: 21 and 22.8. The TCR of claim 1 , wherein the TCR comprises:a) SEQ ID NO: 23 and 24 orb) SEQ ID NO: 25 and 26.9. An isolated or purified polypeptide comprising a functional portion of the TCR of claim 1 , wherein the functional portion comprises the amino acid sequences of SEQ ID NOs: 13-18.10. The isolated or purified polypeptide of claim 9 , wherein the portion comprises the amino acid sequences of SEQ ID NOs ...

Chimeric antigen receptor for bispecific activation and targeting of t lymphocytes

Embodiments of the invention include methods and compositions related to improved cells encoding a chimeric antigen receptor that is specific for two or more antigens. In certain aspects the receptor encompasses two or more non-identical antigen recognition domains. The antigens are tumor antigens, in particular embodiments.

CHIMERIC ANTIGEN RECEPTORS WITH AN OPTIMIZED HINGE REGION

The present invention relates to multi-functional proteins which comprise (i) a signal peptide, (ii) a target specific recognition domain, (iii) a linker region, connecting domain (ii) and domain (iv) which comprises a specific modified hinge region of the human CD8 alpha-chain, and (iv) an effector domain. The present invention furthermore relates to nucleic acids encoding the proteins, expression constructs for expressing the protein in a host cell and host cells. The proteins of the invention are chimeric antigen receptors with an optimized linker or hinge region that are suitable for generating target-specific effector cells, for use as a medicament, in particular in the treatment of cancer and in adoptive, target-cell specific immunotherapy. 1. A protein comprising(i) a signal peptide;(ii) a target specific recognition domain;(iii) a linker region, connecting domain (ii) and domain (iv), the amino acid sequence of SEQ ID NO. 2,', 'an amino acid sequence with at least 95% sequence identity to SEQ ID NO. 2 under the proviso that amino acid residue 48 is not a cysteine and is a serine, and', 'an amino acid sequence that differs in one, two or three amino acid residues from the amino acid sequence of SEQ ID NO. 2 under the proviso that amino acid residue 48 is not a cysteine and is a serine; and, 'wherein the linker region does not contain cysteine residue(s) and is selected from the following 'wherein the effector domain (iv) comprises, or is, a fusion of a fragment of a human costimulatory receptor fused to a fragment of a zeta-chain of a human CD3 complex of a T-cell receptor.', '(iv) an effector domain comprising a transmembrane region and one or more intracellular signaling domains,'}2. The protein of claim 1 , wherein the target is a cell or a virus and wherein the target specific recognition domain (ii) binds an antigen claim 1 , receptor claim 1 , peptide ligand or protein ligand of the target.3. The protein of claim 1 , wherein the target specific ...

ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR VARIANT III CHIMERIC ANTIGEN RECEPTORS AND USE OF SAME FOR THE TREATMENT OF CANCER

The disclosure provides chimeric antigen receptors (CARs) comprising an antigen binding domain of human antibody 139, an extracellular hinge domain, a transmembrane domain, and an intracellular domain T cell receptor signaling domain. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are also disclosed. 1. A chimeric antigen receptor (CAR) comprising an antigen binding domain of human antibody 139 , an extracellular hinge domain , a transmembrane domain , and an intracellular T cell signaling domain.2. The CAR according to claim 1 , wherein the antigen binding domain comprises a light chain variable region comprising SEQ ID NO: 1.3. The CAR according to claim 1 , wherein the antigen binding domain comprises a heavy chain variable region comprising SEQ ID NO: 2.4. The CAR according to claim 1 , wherein the antigen binding domain comprises a linker peptide comprising SEQ ID NO: 3.5. The CAR according to claim 1 , wherein the antigen binding domain comprises a leader sequence comprising SEQ ID NO: 4.6. The CAR according to claim 1 , wherein the antigen binding domain comprises SEQ ID NO: 5.7. The CAR according to claim 1 , further comprising an intracellular hinge domain.8. The CAR according to claim 1 , wherein the extracellular hinge domain and transmembrane domain comprise CD8 (SEQ ID NO: 6).9. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises CD28 claim 1 , 4-1BB claim 1 , and/or CD3 (SEQ ID NO: 7).10. The CAR according to claim 1 , wherein the extracellular hinge domain claim 1 , transmembrane domain claim 1 , and intracellular T cell signaling domain comprise CD28 (SEQ ID NO: 8) and/or CD3t (SEQ ID NO: 9).11. The CAR according to comprising an amino acid sequence ...

Non-naturally occurring t cell receptors

A T cell receptor (TCR) having the property of binding to the gp100 YLEPGPVTA peptide-HLA-A2 complex and comprising a TCR alpha variable domain and/or a TCR beta variable domain, characterized in that the domains are mutated relative to a TCR having the extracellular alpha and beta chain sequences SEQ ID NOs: 2 and that the TCR has a binding affinity for, and/or a binding half-life for, the YLEPGPVTA-HLA-A2 complex at least double that of a reference TCR. Embodiments of the invention such as the use of such TCRs in adoptive therapy, and fusions of such TCRs with therapeutic agents are also described.

Novel constructs for chimeric antigen receptors

The present disclosure pertains to immune cells comprising chimeric antigen receptors (CARs) and methods of using immune cells comprising CARs.

Modified Cell Expressing Therapeutic Agent and Uses thereof

Compositions and methods for enhancing T cell response which increases the efficacy of CAR T cell therapy for treating cancer are described. Embodiments include a modified cell comprising an isolated nucleic acid comprising a first nucleic acid and a second nucleic acid, the first nucleic acid encoding a chimeric antigen receptor (CAR), the second nucleic acid encoding a therapeutic agent comprising at least one of IFN-, IL-2, IL-6, IL-7, IL-15, IL-17, and IL-23. The modified cell expresses and secretes the therapeutic agent. 119-. (canceled)20. A pharmaceutical composition comprising modified T cells , wherein the modified T cells comprise chimeric antigen receptor (CAR) and an exogenous polynucleotide encoding one or more proteins , the one or more proteins comprising IFNγ.21. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises SEQ ID NO: 469 and a polynucleotide encoding SEQ ID NO: 328.22. The pharmaceutical composition of claim 20 , wherein the modified T cells express and secrete the one or more proteins in response to activation of the modified T cells claim 20 , hypoxia claim 20 , or a combination thereof.23. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide is present in the modified T cell in a recombinant DNA construct claim 20 , in an mRNA claim 20 , or in a viral vector.24. The pharmaceutical composition of claim 20 , wherein the one or more proteins further comprise IL-6.25. The pharmaceutical composition of claim 24 , wherein the exogenous polynucleotide comprises a polynucleotide encoding SEQ ID NOS: 287 and a polynucleotide encoding SEQ ID NO: 328.26. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises a promoter comprising a binding site for a transcription modulator that modulates the expression and/or secretion of the one or more proteins in the modified T cells.27. The pharmaceutical composition of claim 26 , wherein the transcription ...

RESTIMULATION OF CRYOPRESERVED TUMOR INFILTRATING LYMPHOCYTES

The present disclosure provides methods for re-stimulating TIL populations that lead to improved phenotype and increased metabolic health of the TILs and provides methods of assaying for TIL populations to determine suitability for more efficacious infusion after re-stimulation. 1. A method for treating a subject with a cancer comprising administering expanded tumor infiltrating lymphocytes (TILs) comprising:(a) performing a first expansion by (i) thawing cryopreserved dissociated tumor materials comprising a first population of TILs obtained from a tumor that was resected from the subject, and (ii) culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs;(b) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, and wherein the second expansion is performed for about 7 to 14 days in order to obtain the third population of TILs;(c) harvesting the third population of TILs obtained from step (b);(d) transferring the harvested third population of TILs from step (c) into an infusion bag;(e) cryopreserving the infusion bag comprising the harvested TIL population from step (d) using a cryopreservation process; and(f) administering a therapeutically effective dosage of the third population of TILs to the subject.2. The method according to claim 1 , wherein the dissociated tumor materials comprise a tumor digest.3. The method according to claim 1 , wherein obtaining the dissociated tumor materials comprises fragmenting the tumor resected from the subject into one or more tumor fragments.4. The method according to claim 1 , wherein obtaining the dissociated tumor materials comprises mechanically disrupting the tumor resected from the subject.5. The method according to claim 1 , wherein ...

CD19 SPECIFIC CHIMERIC ANTIGEN RECEPTOR AND USES THEREOF

The present invention relates to chimeric antigen receptors (CAR). CARs are able to redirect immune cell specificity and reactivity toward a selected target exploiting the ligand-binding domain properties. In particular, the present invention relates to a Chimeric Antigen Receptor in which extracellular ligand binding is a scFV derived from a CD19 monoclonal antibody, preferably 4G7. The present invention also relates to polynucleotides, vectors encoding said CAR and isolated cells expressing said CAR at their surface. The present invention also relates to methods for engineering immune cells; expressing 4G7-CAR at their surface which confers a prolonged “activated” state on the transduced cell. The present invention is particularly useful for the treatment of B-cells lymphomas and leukemia. 1. (canceled)2. A combination therapy comprising:(a) an engineered T-cell expressing a CD19-specific chimeric antigen receptor (CAR); and(b) an antibody.3. The combination therapy of claim 2 , wherein the antibody is the CAMPATH antibody.4. The combination therapy of claim 2 , wherein the CD19-specific CAR comprises at least one extracellular ligand binding domain claim 2 , a transmembrane domain claim 2 , and at least one intracellular signaling domain.5. The combination therapy of claim 4 , wherein the extracellular ligand binding of the CD19-specific CAR comprises an amino acid sequence of SEQ ID NOs: 7 or 8.6. The combination therapy of claim 4 , wherein the at least one intracellular signaling domain of the CD19-specific CAR is a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 10.7. The combination therapy of claim 4 , wherein the transmembrane domain of the CD19-specific CAR comprises a human CD8 alpha chain transmembrane and stalk domain comprising the amino acid sequence of SEQ ID NO: 13.8. The combination therapy of claim 4 , wherein the CD19-specific CAR comprises a second intracellular signaling domain.9. The combination therapy of claim 8 , ...

BISPECIFIC CHIMERIC ANTIGEN RECEPTORS AND THEIR APPLICATION IN THE TREATMENT OF TUMOR

The embodiments of the present invention provide a bispecific chimeric antigen receptor, consisting of a signal peptide, two specific antigen-binding fragments, an extracellular spacer region, a transmembrane region, an intracellular co-stimulatory signaling domain, the first antigen that is recognized and bound by the specific antigen-binding fragments is a member selected from the group consisting of CD19, CD20, CD22, CD33, CD269, CD138, CD79a, CD79b, CD23, ROR1, CD30, B cell surface antibody light chain, CD44, CD123, Lewis Y, CD7 and CD46; the second antigen that is recognized and bound by the specific antigen-binding fragments is CD38, the two specific antigen-binding fragments is linked by a linker peptide, the bispecific chimeric antigen receptor can recognize respectively two kinds of tumor-associated antigens by constructing low affinity chimeric antigen receptors and high affinity chimeric antigen receptors and have very strong specificity. In addition, the embodiments of the present invention also provide a use of the bispecific chimeric antigen receptor in the treatment of tumors. 1. A chimeric antigen receptor , wherein: consisting of a signal peptide , two specific antigen-binding fragments , an extracellular spacer region , a transmembrane region , an intracellular co-stimulatory signaling domain , the first antigen that is recognized and bound by the specific antigen-binding fragments is a member selected from the group consisting of CD19 , CD20 , CD22 , CD33 , CD269 , CD138 , CD79a , CD79b , CD23 , ROR1 , CD30 , B cell surface antibody light chain , CD44 , CD123 , Lewis Y , CD7 and CD46; the second antigen that is recognized and bound by the specific antigen-binding fragments is CD38 , the two specific antigen-binding fragments is linked by a linker peptide.2. The chimeric antigen receptor of claim 1 , wherein: the chimeric antigen receptor is formed by a cell membrane localization signal peptide claim 1 , a CD269 specific antigen-binding fragment ...

TECHNIQUES FOR GENERATING CELL-BASED THERAPEUTICS USING RECOMBINANT T CELL RECEPTOR GENES

The present technology relates generally to compositions and methods for creating recombinant T cell receptor (TCR) libraries and methods of their therapeutic use. The compositions and methods of the present technology are useful for rapid isolation of antigen-specific TCR repertoires as personalized, targeted therapies for cancer and viral infection. 1. A recombinant T cell receptor (TCR) library vector comprising:(a) a vector backbone, optionally wherein the vector backbone is selected from a group consisting of a retroviral, a lentiviral, an adenoviral, and an adeno-associated viral vector backbone; and '(ii) a first polynucleotide encoding a TCRγ polypeptide and a second polynucleotide encoding a TCRδ polypeptide;', '(b) (i) a first polynucleotide encoding a TCRα polypeptide and a second polynucleotide encoding a TCRβ polypeptide; or'}wherein the first and second polynucleotides are a cognate pair, and wherein the first polynucleotide and the second polynucleotide are derived from mRNA isolated from a single lysed T cell that is present in a compartment, optionally whereinthe compartment has a volume of 5 nL or less, orthe compartment is an emulsion droplet or a well, optionally wherein the well is located in a printed polymer slide, a plastic plate, a microtiter plate, or a gel, orwherein the vector is circularized.2. The vector of claim 1 , wherein the mRNA of the single lysed T cell is isolated using an mRNA capture reagent or reverse transcription-PCR (RT-PCR) claim 1 , optionally whereinthe first polynucleotide and the second polynucleotide are operably linked via a linker polynucleotide or by reverse transcription and PCR amplification of the T cell mRNA, orthe mRNA capture reagent is selected from the group consisting of a poly(dT) coated bead, an oligonucleotide-coated bead, a hydrogel bead, and a printed oligo on the surface of a microarray well.3. (canceled)4. The vector of claim 1 , wherein the first polynucleotide and the second polynucleotide have ...

IL-13 RECEPTOR ALPHA 2 (IL13RA2) CHIMERIC ANTIGEN RECEPTOR FOR TUMOR SPECIFIC T CELL IMMUNOTHERAPY

Some embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to human extracellular domains of the IL-13 alpha 2 (IL13Ra2) receptor, cells containing such CARs, and methods of cell-based immunotherapy targeting cancer cells, such as cells of solid tumors. 1. A nucleic acid encoding a chimeric antigen receptor , the chimeric antigen receptor comprising:a ligand binding domain that binds to and/or interacts with an IL-13 alpha 2 (IL13Rα2) receptor;a polypeptide spacer between the ligand binding domain and a transmembrane domain;the transmembrane domain; andintracellular signaling region.266-. (canceled) This application claims priority to U.S. Prov. App. No. 62/643,055 filed Mar. 14, 2018 entitled “IL-13 RECEPTOR ALPHA 2 (IL3RA2) CHIMERIC ANTIGEN RECEPTOR FOR TUMOR SPECIFIC T CELL IMMUNOTHERAPY” which is hereby expressly incorporated by reference in its entirety.The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SCRI169WOSEQLIST, created Mar. 12, 2019, which is approximately 62 Kb in size. The information in the electronic format of the Sequence Listing is hereby expressly incorporated by reference in its entirety.Some embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to human extracellular domains of an IL-13 alpha 2 (IL13Ra2) receptor, to cells containing such CARs, and to methods of cell-based immunotherapy targeting cancer cells, such as cells of solid tumors.Despite significant advances in the understanding of brain cancer, during the last decade, the mortality rate has remained consistent and new innovative therapies are urgently needed. To date, T cell immunotherapy has emerged as a promising cancer therapy supported by remarkable clinical data reporting complete remission in patients with B cell malignancies after ...

Lymphocyte Cell Lines and Uses Thereof

Embodiments described herein relate to compositions including genetically modified CAR cells and uses thereof for treating cancer. Some embodiments of the present disclosure relate to compositions and methods for T cell response enhancement and/or CAR cell preparation. For example, a method may include obtaining cells comprising a CAR and culturing the cells in the presence of an agent that is recognized by the extracellular domain of the CAR. 1. A method comprising:providing T cells comprising a chimeric antigen receptor (CAR); andculturing the T cells in the presence of an agent that an extracellular domain of the CAR binds to obtain CAR T cells.2. The method of claim 1 , wherein the agent binds the extracellular domain of the CAR and mediates a response by the T cells comprising the CAR.3. The method of claim 1 , wherein the agent is an extracellular domain of the antigen.4. The method of claim 3 , wherein the antigen is Epidermal growth factor receptor (EGFR) claim 3 , Variant III of the epidermal growth factor receptor (EGFRvIII) claim 3 , Human epidermal growth factor receptor 2 (HER2) claim 3 , Mesothelin (MSLN) claim 3 , Prostate-specific membrane antigen (PSMA) claim 3 , Carcinoembryonic antigen (CEA) claim 3 , Disialoganglioside 2 (GD2) claim 3 , Interleukin-13Ra2 (IL13Rα2) claim 3 , Glypican-3 (GPC3) claim 3 , Carbonic anhydrase IX (CAIX) claim 3 , L1 cell adhesion molecule (L1-CAM) claim 3 , Cancer antigen 125 (CA125) claim 3 , Cluster of differentiation 133 (CD133) claim 3 , Fibroblast activation protein (FAP) claim 3 , Cancer/testis antigen 1B (CTAG1B) claim 3 , Mucin 1 (MUC1) claim 3 , Folate receptor-α (FR-α) claim 3 , CD19 claim 3 , FZD10 claim 3 , TSHR claim 3 , PRLR claim 3 , Muc 17 claim 3 , GUCY2C claim 3 , CD207 claim 3 , CD3 claim 3 , CD5 claim 3 , B-Cell Maturation Antigen (BCMA) claim 3 , or CD4.5. The method of claim 1 , wherein a ratio of an amount of the agent and a number of the CAR T cells after culturing with the agent is 1:5000 to 1:5 ...

Modified Monocytes/Macrophage Expressing Chimeric Antigen Receptors and Uses Thereof

The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression. 144-. (canceled)45. A pharmaceutical composition comprising: (i) at least 50% of the cells in the population of cells are CD14+ or CD11b+, and', '(ii) the population of cells has been depleted for cells expressing CD3 and CD19 and, '(a) a population of modified human cells comprising a chimeric antigen receptor (CAR), wherein(b) a pharmaceutically acceptable excipient.46. The pharmaceutical composition of claim 45 , wherein the CAR comprises an antigen binding domain claim 45 , a transmembrane domain and an intracellular domain of a stimulatory and/or co-stimulatory molecule.47. The pharmaceutical composition of claim 46 , wherein the antigen binding domain comprises an anti-HER2 antigen binding domain claim 46 , an anti-mesothelin antigen binding domain claim 46 , an anti-CD19 antigen binding domain or an anti-PSMA antigen binding domain.48. The pharmaceutical composition of claim 46 , wherein the antigen binding domain of the CAR comprises an antibody selected from the group consisting of a monoclonal antibody claim 46 , a polyclonal antibody claim 46 , a synthetic antibody claim 46 , human antibody claim 46 , humanized antibody claim 46 , single domain antibody claim 46 , single chain variable fragment claim 46 , and antigen-binding fragments thereof.49. The pharmaceutical composition of claim 46 , wherein the transmembrane domain of the CAR comprises a CD8 or CD28 transmembrane domain.50. The ...

Modified Monocytes/Macrophage Expressing Chimeric Antigen Receptors and Uses Thereof

The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression. 144-. (canceled)45. A pharmaceutical composition comprising: wherein at least 70% of the cells in the population of cells express the CAR,', 'wherein the modified human cells are modified human macrophages and/or modified human monocytes, and, '(a) a population of modified human cells comprising a chimeric antigen receptor (CAR),'}(b) a pharmaceutically acceptable excipient.46. The pharmaceutical composition of claim 45 , wherein the CAR comprises an antigen binding domain claim 45 , a transmembrane domain and an intracellular domain of a stimulatory and/or co-stimulatory molecule.47. The pharmaceutical composition of claim 45 , wherein the antigen binding domain comprises an anti-HER2 antigen binding domain claim 45 , an anti-mesothelin antigen binding domain claim 45 , an anti-PSMA antigen binding domain claim 45 , or an anti-CD19 antigen binding domain.48. The pharmaceutical composition of claim 46 , wherein the antigen binding domain of the CAR comprises an antibody selected from the group consisting of a monoclonal antibody claim 46 , a polyclonal antibody claim 46 , a synthetic antibody claim 46 , human antibody claim 46 , humanized antibody claim 46 , single domain antibody claim 46 , single chain variable fragment claim 46 , and antigen-binding fragments thereof.49. The pharmaceutical composition of claim 46 , wherein the transmembrane domain of the CAR comprises a CD8 or CD28 transmembrane domain.50. ...

Chimeric antigen receptor and its use

In a first aspect, the present invention relates to a recombinant polypeptide containing a domain comprising at least two antibody units whereby the first antibody unit is an an anti-CD30 single chain antibody unit while the second antibody unit is a antibody unit being specific for an antigen present on the surface of a pre-determined target cell. In particular, the present invention relates to a recombinant polypeptide containing at least the following domains starting from the N-terminus to the C-terminus: a first domain containing an anti-CD30 single chain anti-body unit, in particular, HRS3 scFv of SEQ ID No. 2 or homologs thereof having at least 70% identity with SEQ ID No. 2 binding specifically to CD30, and an antibody unit said antibody unit being specific for an antigen present on the surface of a predetermined target cell, in particular, being specific for a tumor-associated antigen; optionally a spacer domain; a trans-membrane domain; and a cytoplasmatic signalling domain. In a further aspect, the present invention relates to a nucleic acid molecule encoding the polypeptide according to the present invention, as well as vectors and cells containing the same. Moreover, lymphocytes are provided, in particular T-cells like CD8′ or a CD4* T-cell expressing on its surface chimeric antigen receptors containing an anti-CD30 single chain antibody unit and an antibody unit whereby said antibody unit being specific for an antigen present on the surface of a predetermined target cell. Immune cells modified with the polypeptide show improved functions, in particular in the treatment of cancer, in particular CD30− cancer. That is, the cells are for use in adapted cell therapy for treating cancer in a subject in need thereof.

Homodimer-type bispecific antibody targeting cd19 and cd3, and preparation method therefor and application thereof

Provided is a tetravalent, homodimer-type bispecific antibody molecule that targets both immune effector cell antigen CD3 and tumor-related antigen CD19. The bispecific antibody molecule comprises first and second single-chain Fv and Fc fragments in sequence from the N-terminus to the C-terminus, wherein the first single-chain Fv can specifically bind to CD19, the second single-chain Fv can specifically bind to CD3, the first and second single-chains Fv are connected by means of a linker peptide, the second single-chain Fv and Fc fragments are directly connected to each other or connected by means of a linker peptide; and the Fc fragment does not have effector functions such as CDC, ADCC, and ADCP. The bispecific antibody can significantly inhibit or kill tumor cells, and has toxic and side effects that may be caused by excessive activation of effector cells; in addition, such bispecific antibody is of homodimer type, without the problem of heavy chain and light chain mismatch; the purification step is simple and efficient, the expression is high, and the physical and chemical properties as well as in vivo stability of the antibody are significantly improved.

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST EPITHELIAL OVARIAN CANCER AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has cancer , comprising administering to said patient a composition comprising a population of activated T cells that kill cancer cells in the patient that present a peptide , wherein said peptide consists of the amino acid sequence of SEQ ID NO: 130 , 1 , 122 , 128 , 2 , 86 , 98 , 119 , 147 , 3-81 , 83 , 85 , 87-97 , 99-118 , 120 , 121 , 123-127 , 129 , 131-146 , or 148-549 , wherein said cancer is selected from the group consisting of ovarian cancer , non-small cell lung cancer , small cell lung cancer , kidney cancer , brain cancer , colon or rectum cancer , stomach cancer , liver cancer , pancreatic cancer , prostate cancer , leukemia , breast cancer , Merkel cell carcinoma , melanoma , esophageal cancer , urinary bladder cancer , uterine cancer , gallbladder cancer , and bile duct cancer.2. The method of claim 1 , wherein the T cells are autologous to the patient.3. The method of claim 1 , wherein the T cells are obtained from a healthy donor.4. The method of claim 1 , wherein the T cells are derived from tumor infiltrating lymphocytes or peripheral blood mononuclear cells.5. The method of claim 1 , further comprising expanding T cells in vitro.6. The method of claim 1 , wherein the peptide is in ...

Novel peptides and combination of peptides for use in immunotherapy against epithelial ovarian cancer and other cancers

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

TARGETED REPLACEMENT OF ENDOGENOUS T CELL RECEPTORS

Provided herein are methods and compositions for editing the genome of a human T cell. In some embodiments, a heterologous T cell receptor (TCR)-β chain and a heterologous TCR-α chain are inserted into exon 1 of a TCR subunit constant gene in the genome of the T cell. 1. A primary human T cell comprising: an endogenous T cell receptor alpha subunit constant gene (TRAC), and', 'an endogenous T cell receptor beta subunit constant gene (TRBC),, 'at least one nucleic acid sequence comprising at least one heterologous gene non-virally inserted into at least one target region of one or both ofwherein the at least one heterologous gene comprises at least one of: (1) a variable region of a heterologous T cell receptor alpha (TCR-α) chain gene and (2) a variable region of a heterologous T cell receptor beta (TCR-β) chaingene.2. The T cell of claim 1 , wherein the T cell does not comprise a viral vector for introducing the at least one nucleic acid sequence to the T cell.3. The T cell of claim 1 , wherein the at least one nucleic acid sequence is at least 1.5 kb in size.4. The T cell of claim 1 , wherein the at least one nucleic acid sequence is at least 500 bp in size.5. The T cell of claim 1 , wherein the target region is in exon 1 claim 1 , 2 claim 1 , or 3 of TRAC.6. The T cell of claim 1 , wherein the target region is in exon 1 claim 1 , 2 claim 1 , or 3 of TRBC.7. The T cell of claim 1 , wherein the T cell is a CD8 T cell or a CD4 T cell.8. The T cell of claim 1 , wherein the at least one heterologous gene comprises at least one of: (1) a) variable region or b) variable region and constant region of the heterologous T cell receptor alpha (TCR-α) chain gene and (2) a) variable region or b) variable region and constant region of the heterologous T cell receptor beta (TCR-β) chain gene.9. The T cell of claim 8 , wherein the at least one heterologous gene comprises each of: (1) the a) variable region or b) variable region and constant region of the heterologous T cell ...

A*03 restricted peptides for use in immunotherapy against cancers and related methods

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST PROSTATE CANCER AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has cancer , comprising administering to said patient a population of activated T cells that kill cancer cells that present a peptide consisting of the amino acid sequence selected from SEQ ID NO: 24 , wherein said cancer is selected from liver cancer , benign prostate hyperplasia , and prostate cancer.2. The method of claim 1 , wherein the T cells are autologous to the patient.3. The method of claim 1 , wherein the T cells are obtained from a healthy donor.4. The method of claim 1 , wherein the T cells are obtained from tumor infiltrating lymphocytes or peripheral blood mononuclear cells.5. The method of claim 1 , wherein the activated T cells are expanded in vitro.6. The method of claim 1 , wherein the population of activated T cells are administered in the form of a composition.7. The method of claim 6 , wherein the composition further comprises an adjuvant.8. The method of claim 7 , wherein the adjuvant is selected from anti-CD40 antibody claim 7 , imiquimod claim 7 , resiquimod claim 7 , GM-CSF claim 7 , cyclophosphamide claim 7 , sunitinib claim 7 , bevacizumab claim 7 , interferon-alpha claim 7 , interferon-beta claim 7 , CpG oligonucleotides and derivatives claim 7 , poly-(I:C) and derivatives ...

Anti-hsp70 specific chimeric antigen receptors (cars) for cancer immunotherapy

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from an anti-HSP70 monoclonal antibody, conferring specific immunity against HSP70 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating in particular leukemia.

NOVEL CONSTRUCTS FOR CHIMERIC ANTIGEN RECEPTORS

The present disclosure pertains to immune cells comprising chimeric antigen receptors (CARs) and methods of using immune cells comprising CARs. 180-. (canceled)81. A method of modifying a macrophage or monocyte comprising delivering to the macrophage or monocyte: (a) an extracellular domain,', '(b) a transmembrane domain, and', '(c) an intracellular domain, and, '(i) a viral vector comprising one or more nucleic acid sequences encoding a chimeric antigen receptor (CAR) comprising(ii) at least one Vpx protein,thereby producing a modified macrophage or monocyte that exhibits increased CAR expression relative to a macrophage or monocyte comprising a CAR delivered by a viral vector and not delivered at least one Vpx protein.82. The method of claim 81 , wherein the viral vector comprises or is a lentiviral vector.83. The method of claim 81 , wherein the modified macrophage or monocyte exhibits increased CAR expression of about 40% or greater relative to a macrophage or monocyte not delivered at least one Vpx protein.84. The method of claim 81 , wherein the modified macrophage or monocyte exhibits CAR expression for an extended time period of at least 5 days relative to an unmodified macrophage or monocyte.85. The method of claim 81 , wherein the modified macrophage or monocyte does not exhibit an M1 phenotype relative to a macrophage or monocyte not delivered at least one Vpx protein.86. The method of claim 85 , wherein the modified macrophage or monocyte does not exhibit increased expression of one or more markers of M1 phenotype relative to a macrophage or monocyte not delivered at least one Vpx protein.87. The method of claim 86 , wherein the one or more markers of M1 phenotype comprise or are one or more of CD86 claim 86 , CD80 claim 86 , MHC II claim 86 , IL-1R claim 86 , TLR2 claim 86 , TLR4 claim 86 , iNOS claim 86 , SOCS3 claim 86 , CD83 claim 86 , PD-L1 claim 86 , CD69 claim 86 , MHC I claim 86 , CD64 claim 86 , CD32 claim 86 , CD16 claim 86 , IL1R claim 86 , a ...

Engineered Cells Expressing Anti-Viral T Cell Receptors and Methods of Use Thereof

Provided herein are compositions comprising recombinant mammalian cells that express recombinant T cell rectors with specificity against EBV or CMV peptide:MHC antigens. Also provided are therapeutic methods of using the recombinant mammalian cells as cell therapies against viral infections. 1. A method of identifying T cell receptors specific to an antigen of interest , comprising:providing primary immune cells from at least one mammalian donor;generating a plurality of recombinant fusion polynucleotides, wherein each of the recombinant fusion polynucleotides comprises a first polynucleotide encoding a beta chain variable domain and a second polynucleotide encoding an alpha chain variable domain, and wherein said beta chain variable domain and alpha chain variable domain on each of said plurality of recombinant fusion polynucleotides are a cognate pair from one of said isolated primary immune cells;generating recombinant T cell receptor expression constructs comprising the plurality of recombinant fusion polynucleotides;introducing said recombinant T cell receptor expression constructs into a plurality of host cells;inducing expression of recombinant T cell receptors from said recombinant T cell receptor expression constructs in said plurality of host cells, thereby generating the recombinant T cell receptor library comprising said plurality of host cells expressing the recombinant T cell receptors;optionally, enriching a first subset of the plurality of host cells based on their binding property to a soluble complex comprising MHC and an antigen of interest;exposing said recombinant T cell receptor library or the first subset of the plurality of host cells to target cells expressing the antigen of interest;selecting a second subset of the host cells from the recombinant T cell receptor library or the first subset using activation markers; andsequencing T cell receptor transcripts isolated from the second subset of the host cells, thereby identifying T cell ...

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST VARIOUS CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of treating a patient who has cancer , comprising administering to the patient an effective amount of an antibody specifically binding to an MHC class I or II molecule complexed with an antigen consisting of the amino acid sequence of VQLDSIEDLEV (SEQ ID NO: 32) ,wherein said cancer is selected from the group consisting of glioblastoma, breast cancer, colorectal cancer, renal cell carcinoma, chronic lymphocytic leukemia, hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, Non-Hodgkin lymphoma, acute myeloid leukemia, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, gallbladder cancer and cholangiocarcinoma, melanoma, gastric cancer, urinary bladder cancer, head- and neck squamous cell carcinoma, and uterine cancer.2. The method of claim 1 , wherein the antibody is a polyclonal antibody claim 1 , a monoclonal antibody claim 1 , a bi-specific antibody claim 1 , or a chimeric antibody.3. The method of claim 1 , wherein the antibody binds to the HLA-restricted antigen with a binding affinity of below 20 nanomolar.4. The method of claim 1 , wherein the antibody binds to the MHC class I molecule complexed with the HLA-restricted antigen.5. The method of claim 1 , wherein the antibody is humanized.6. The ...

Novel peptides and combination of peptides for use in immunotherapy against hepatocellular carcinoma (hcc) and other cancers

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. In particular, the present invention relates to several novel peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses or as targets for the development of pharmaceutically/immunologically active compounds and cells.

Methods for Identifying and Isolating Cells Expressing a Polypeptide

The invention relates to novel polypeptides and cells comprising the polypeptides. The polypeptides and cells are used in methods to identify and/or isolate cells producing a protein with specific biological functions. In particular, the methods may be used for identifying, selecting, and isolating cells producing antigen-specific monoclonal antibodies. 1216-. (canceled)217. A method of producing a host cell , comprising:(a) transfecting a cell with a polynucleotide that encodes a polypeptide, wherein the polypeptide comprises (i) an extracellular portion comprising an immunoglobulin heavy chain constant region comprising CH2 and CH3 domains; and (ii) a non-immunoglobulin transmembrane portion, wherein the polypeptide comprises a sequence at least 80% identical to SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:31, or SEQ NO:32; and(b) incubating the cell to allow expression of the polypeptide.218. The method of claim 217 , wherein the polypeptide comprises a sequence at least 80% identical to SEQ ID NO:12.219. The method of claim 217 , wherein the polypeptide comprises SEQ ID NO:1.0 claim 217 , SEQ ID NO:12 claim 217 , SEQ ID NO:22 claim 217 , SEQ ID NO:23 claim 217 , SEQ ID NO:26 claim 217 , SEQ ID NO:28 claim 217 , SEQ ID NO:30 claim 217 , SEQ ID NO:31 claim 217 , or SEQ ID NO:32.220. The method of claim 217 , wherein the polypeptide comprises SEQ ID NO:12.221. The method of claim 217 , wherein the cell is transiently transfected.222. The method of claim 217 , wherein the cell is stably transfected.223. The method of claim 217 , wherein the polynucleotide encoding the polypeptide is integrated into the genome of the cell.224. The method of claim 217 , wherein the polynucleotide encoding the polypeptide is stably expressed.225. The method of claim 217 , wherein the polypeptide is membrane-bound and expressed on the surface of the cell.226. The method of claim 217 , further comprising (c) detecting ...

Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A peptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 640 , and variant sequences thereof which are at least 88% homologous to SEQ ID No. 1 to SEQ ID No. 640 , wherein said variant binds to molecule(s) of the major histocompatibility complex (MHC) and/or induces T cells cross-reacting with said variant peptide; and a pharmaceutical acceptable salt thereof , wherein said peptide is not a full-length polypeptide.2. The peptide or variant according to claim 1 , wherein said peptide has the ability to bind to a MHC class-I or -II molecule claim 1 , and wherein said peptide claim 1 , when bound to said MHC claim 1 , is capable of being recognized by CD4 and/or CD8 T cells.3. The peptide or variant thereof according to claim 1 , wherein the amino acid sequence thereof comprises a continuous stretch of amino acids according to the group of SEQ ID No. 1 to SEQ ID No. 640.4. The peptide or variant thereof according to claim 1 , wherein said peptide or variant thereof has an overall length of from 8 to 100 claim 1 , optionally from 8 to 30 claim 1 , and optionally from 8 to 16 amino acids claim 1 , and optionally wherein the peptide consists or consists essentially of an amino acid sequence according to the group ...

Compositions and Methods for Treating Cancer

The invention provides compositions and methods for treating ovarian cancer. Specifically, the invention relates to administering a genetically modified T cell having α-folate receptor (FRα) binding domain and 4-1BB (CD137) costimulatory domain to treat ovarian cancer. 1. An isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR) , wherein the isolated nucleic acid sequence comprises a nucleic acid sequence encoding an α-folate receptor (FRα) antibody comprising the amino acid sequence of SEQ ID NO: 23.2. The isolated nucleic acid sequence of claim 1 , wherein the CAR further comprises a CD3 zeta signaling domain.3. The isolated nucleic acid sequence of claim 2 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO: 19.4. The isolated nucleic acid sequence of claim 2 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence of SEQ ID NO: 7.5. The isolated nucleic acid sequence of claim 1 , wherein the CAR further comprises a transmembrane domain.6. An isolated chimeric antigen receptor (CAR) claim 1 , wherein the CAR comprises an anti-folate receptor (FRα) antibody comprising the amino acid sequence of SEQ ID NO: 23.7. The isolated CAR of claim 6 , wherein the CAR further comprises a CD3 zeta signaling domain.8. The isolated CAR of claim 7 , wherein the CD3 zeta signaling domain comprises an amino acid sequence of SEQ ID NO: 19.9. The isolated CAR of claim 7 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence of SEQ ID NO: 7.10. The isolated CAR of claim 6 , wherein the CAR further comprises a transmembrane domain.11. A method for providing anti-tumor immunity in a subject claim 6 , the method comprising:{'claim-ref': {'@idref': 'CLM-00006', 'claim 6'}, 'administering to the subject an effective amount of a T cell comprising the CAR of , thereby providing anti-tumor immunity in the subject.'}12. The method of claim 11 , wherein the CAR further comprises a 4-1BB ...

Peptides and nanoparticles for intracellular delivery of molecules

The present invention pertains to peptides and peptide-containing complexes/nanoparticles that are useful for stabilizing and delivering cargo molecules such as nucleic acids.

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES AND SCAFFOLDS THEREOF FOR USE IN IMMUNOTHERAPY AGAINST COLORECTAL CARCINOMA (CRC) AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T-cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. An expression vector expressing a nucleic acid encoding a peptide consisting of the amino acid sequence of KQFEGTVEI (SEQ ID NO: 138) or ALAAARVEL (SEQ ID NO: 17).2. A recombinant host cell comprising the peptide according to .3. A recombinant host cell comprising the nucleic acid according to .4. A recombinant host cell presenting HLA-A*02 on its surface comprising the expression vector according to claim 1 , wherein said host cell is optionally an antigen presenting cell.5. A method for producing a peptide consisting of the amino acid sequence of KQFEGTVEI (SEQ ID NO: 138) or ALAAARVEL (SEQ ID NO: 17) claim 3 , comprising culturing the host cell according to claim 3 , and isolating the peptide from the host cell or its culture medium.6. An in vitro method for producing activated T lymphocytes claim 3 , comprising contacting in vitro T cells with antigen loaded human HLA-A*0201 expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said T cells in an antigen specific manner claim 3 , wherein said antigen is a peptide consisting of the amino acid sequence of KQFEGTVEI (SEQ ID NO: 138) or ALAAARVEL (SEQ ID NO: 17).7. A method of treating a HLA-A* ...

CONSTRUCTION OF CHIMERIC ANTIGEN RECEPTOR TARGETING CD20 ANTIGEN AND ACTIVITY IDENTIFICATION OF ENGINEERED T CELLS THEREOF

Provided are a chimeric antigen receptor targeting CD20 antigen and a preparation method thereof. The extracellular antigen binding domain of the chimeric antigen receptor includes an antibody heavy chain variable region shown in SEQ ID NO: 7 or 9 or 33 and an antibody light chain variable region shown in SEQ ID NO: 11 or 13 or 35, and is capable of killing tumor cells. 1. A chimeric antigen receptor (CAR) wherein the CAR has an antigen binding domain which comprises an antibody heavy chain variable region as shown in SEQ ID NO: 7 or 9 or 33 and an antibody light chain variable region as shown in SEQ ID NO: 11 or 13 or 35.2. The chimeric antigen receptor of claim 1 , whose antigen binding domain is as follows:{'br': None, 'sub': H', 'L, 'V-V'}{'sub': H', 'L, 'wherein Vis an antibody heavy chain variable region; Vis an antibody light chain variable region; and “-” is a linker peptide or a peptide bond.'}3. The chimeric antigen receptor of claim 2 , wherein the amino acid sequence of Vis as shown in SEQ ID NO: 7 claim 2 , and the amino acid sequence of Vis as shown in SEQ ID NO: 11; or{'sub': H', 'L, 'the amino acid sequence of Vis as shown in SEQ ID NO: 9, and the amino acid sequence of Vis as shown in SEQ ID NO: 13, or'}{'sub': H', 'L, 'the amino acid sequence of Vis as shown in SEQ ID NO: 33, and the amino acid sequence of Vis as shown in SEQ ID NO: 35.'}4. A nucleic acid molecule encoding the chimeric antigen receptor (CAR) of .5. The nucleic acid molecule of claim 4 , which comprises a nucleic acid sequence encoding hinge region selected from the group consisting of:(a) a polynucleotide encoding a polypeptide as shown in SEQ ID NO: 17 or 19;(b) a polynucleotide having a sequence as shown in SEQ ID NO: 18 or 20;(c) a polynucleotide having a nucleotide sequence with ≥90% (preferably ≥95%) homologous to the sequence of SEQ ID NO: 18 or 20 and encoding the amino acid sequence of SEQ ID NO: 17 or 19;(d) a polynucleotide complementary to the polynucleotide of any of (a ...

Cll1-specific multi-chain chimeric antigen receptor

The present invention relates to a new generation of chimeric antigen receptors (CAR) referred to as multi-chain CARs, which are made specific to the antigen CLL1. Such CARs aim to redirect immune cell specificity and reactivity toward malignant cells expressing the tumor antigen CLL1. The alpha, beta and gamma polypeptides composing these CARs are designed to assemble in juxtamembrane position, which forms flexible architecture closer to natural receptors, that confers optimal signal transduction. The invention encompasses the polynucleotides, vectors encoding said multi-chain CAR and the isolated cells expressing them at their surface, in particularly for their use in immunotherapy. The invention opens the way to efficient adoptive immunotherapy strategies for treating cancer, especially leukemia.

mAb-DRIVEN CHIMERIC ANTIGEN RECEPTOR SYSTEMS FOR SORTING/DEPLETING ENGINEERED IMMUNE CELLS

A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope. 1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain that comprises a scFv formed by at least a VH chain and a VL chain specific to an antigen , wherein said extracellular binding domain comprises at least one mAb-specific epitope.2. The polypeptide according to claim 1 , wherein said mAb-specific epitope is located between the VH and VL chains.3. The polypeptide according to claim 1 , wherein said VH and VL chains claim 1 , and mAb specific-epitope are bound together by at least one linker and to the transmembrane domain of said CAR by a hinge.4. The polypeptide according to claim 3 , wherein the mAb-specific epitope is joined to the VH and VL chains by two linkers.5. The polypeptide according to claim 1 , wherein the mAb-specific epitope is an epitope to be bound by an epitope-specific mAb for in vitro cell sorting and/or in vivo cell depletion of T cells expressing a CAR comprising such epitope.6. The polypeptide according to claim 1 , wherein the polypeptide comprises one extracellular binding domain claim 1 , wherein said extracellular binding domain further comprises a hinge claim 1 , and said polypeptide further comprisesa transmembrane domain, and,an intracellular domain.7. The polypeptide according to claim 1 , wherein the extracellular binding domain comprises 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 claim 1 , 5 claim 1 , 6 claim 1 , 7 claim 1 , 8 claim 1 , 9 or 10 mAb-specific epitopes.8. The polypeptide according to claim 1 , wherein the extracellular binding domain comprises 1 claim 1 , 2 claim 1 , 3 or claim 1 , 4 mAb-specific epitopes.9. The polypeptide according to claim 1 , wherein the extracellular binding ...

CHIMERIC TRANSMEMBRANE PROTEINS AND USES THEREOF

Provided herein are chimeric transmembrane proteins and proteins, nucleic acids encoding these chimeric transmembrane proteins or proteins, and mammalian cells containing these nucleic acids, and methods of making and using these mammalian cells. 1. A protein comprising a transmembrane domain of an alpha chain of interleukin-7 receptor , with one or more modifications , wherein the transmembrane domain with one or more modifications has a sequence of SEQ ID NO: 2 , 4 , 6 or 8.2. The protein of claim 1 , wherein the protein further comprises an intracellular domain of an alpha chain of interleukin-7 receptor.3. The protein of claim 2 , wherein the intracellular domain comprises a sequence of SEQ ID NO: 45.4. The protein of claim 1 , wherein the protein further comprises an extracellular domain of an alpha chain of interleukin-7 receptor.5. The protein of claim 4 , wherein the extracellular domain comprises a sequence of SEQ ID NO: 11.6. The protein of claim 1 , further comprisingan extracellular interleukin-15 domain; andan extracellular sushi domain from an alpha chain of interleukin-15 receptor.7. The protein of claim 6 , wherein the extracellular interleukin-15 domain comprises a sequence of SEQ ID NO: 22 or SEQ ID NO: 24.8. The protein of claim 6 , wherein the extracellular sushi domain of the alpha chain of interleukin-15 receptor comprises SEQ ID NO: 36 or SEQ ID NO: 37.9. A nucleic acid encoding a protein of .10. A vector comprising the nucleic acid of .11. The vector of claim 10 , further comprising a promoter operably linked to the nucleic acid claim 10 , and optionally claim 10 , an enhancer sequence operably linked to the nucleic acid.12. The vector of claim 10 , further comprising a sequence encoding a chimeric antigen receptor which binds specifically to a tumor antigen.13. The vector of claim 12 , wherein the tumor antigen is selected from the group consisting of: glypican-3 claim 12 , BCMA claim 12 , MAGE claim 12 , MUC16 claim 12 , CD19 claim 12 , WT- ...

CHIMERIC ANTIGEN RECEPTORS, COMPOSITIONS, AND METHODS

This disclosure describes chimeric antigen receptors for expression in a Natural Killer (NK) cell, pharmaceutical compositions that include NK cells (and/or iPSCs) modified to express a chimeric antigen receptor, and methods involving such chimeric antigen receptors. Generally, the chimeric antigen receptor includes an ectodomain that includes an antigen recognition region, a transmembrane domain linked to the ectodomain, and an endodomain linked to the transmembrane domain. The endodomain can include a signaling peptide that activates an NK cell. 1. A chimeric antigen receptor comprising:an ectodomain comprising an antigen recognition region;a transmembrane domain linked to the ectodomain; andan endodomain linked to the transmembrane domain, the endodomain comprising a signaling peptide that activates an NK cell.2. The chimeric antigen receptor of wherein the antigen recognition domain specifically binds an antigen associated with a disease.3. The chimeric antigen receptor of wherein the antigen recognition domain specifically binds a tumor antigen.4. The chimeric antigen receptor of wherein the ectodomain further comprises a signal peptide or leader sequence.5. The chimeric antigen receptor of wherein the ectodomain further comprises a spacer.6. The chimeric antigen receptor of wherein the endodomain comprises a signaling domain of and NK cell membrane-bound signaling adaptor protein.7. The chimeric antigen receptor of wherein the NK cell membrane-bound signaling adaptor protein comprises at least a portion of 2B4 (CD244) claim 6 , CD137 (41BB) claim 6 , IL21 claim 6 , DAP10 claim 6 , DAP12 claim 6 , or CD3ζ.8. The chimeric antigen receptor of wherein the transmembrane domain comprises a transmembrane region of a natural cytotoxicity receptor expressed in NK cells.9. The chimeric antigen receptor of wherein the natural cytotoxicity receptor expressed in NK cells comprises at least a portion of CD16 claim 8 , NKp44 claim 8 , NKp46 claim 8 , NKG2D claim 8 , NKp30 ...

CS1-SPECIFIC CHIMERIC ANTIGEN RECEPTOR ENGINEERED IMMUNE EFFECTOR CELLS

Disclosed herein are chimeric antigen receptors (CAR) that can specifically recognize tumor-associated antigens (TAA) on multiple myelorna (MM) cells. Also disclosed are Mullane effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with MM that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. 14.-. (canceled)5. A nucleic acid sequence encoding a chimeric antigen receptor (CAR) polypeptide , wherein the CAR polypeptide is defined by the formula:{'br': None, 'SP-CS1-HG-TM-CSR-ISD; or'}{'br': None, 'SP-CS1-HG-TM-ISD-CSR'}wherein “SP” represents a signal peptide,wherein “CS1” represents a CS1 antigen binding domain,wherein “HG” represents an optional hinge domain,wherein “TM” represents a transmembrane domain,wherein “CSR” represents a co-stimulatory signaling region,wherein “ISD” represents an intracellular signaling domain, andwherein “-” represents a bivalent linker.6. The nucleic acid sequence of claim 5 , wherein the CS1 antigen binding domain comprises an Fab or a single-chain variable fragment (scFv) of an antibody that specifically binds CS1.7. The nucleic acid sequence of claim 5 , wherein the intracellular signaling domain comprises a CD3 zeta (CD3ζ) signaling domain.8. The nucleic acid sequence of claim 5 , wherein the costimulatory signaling region comprises the cytoplasmic domain of a costimulatory molecule selected from the group consisting of CD28 and 4-1BB.9. A vector comprising the nucleic acid sequence of .10. A cell comprising the vector of .11. The cell of claim 10 , wherein the cell is selected from the group consisting of a T cell claim 10 , a Natural Killer (NK) cell claim 10 , and a cytotoxic T lymphocyte (CTL).12. The cell of claim 11 , wherein the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to CS1.1320.-. ( ...

THERAPEUTIC AGENTS

An immunoresponsive cell, such as a T-cell expressing 1. An immuno-responsive cell expressing (a) a signalling region;', '(b) a co-stimulatory signalling region;', '(c) a transmembrane domain; and', '(d) a binding element that specifically interacts with a first epitope on a target antigen; and, '(i) a second generation chimeric antigen receptor comprising (e) a co-stimulatory signalling region which is different to that of (b);', '(f) a transmembrane domain; and', '(g) a binding element that specifically interacts with a second epitope on a target antigen., '(ii) a chimeric costimulatory receptor comprising'}2. The immuno-responsive cell of which is a T-cell.3. The immuno-responsive cell of wherein the signalling region (a) comprises the intracellular domain of human CD3 [zeta] chain or a variant thereof.4. The immuno-responsive cell of wherein co-stimulatory signalling regions for (b) and (e) are selected from CD28 claim 1 , CD27 ICOS claim 1 , 4-1BB claim 1 , OX40 claim 1 , CD30 claim 1 , GTR claim 1 , HVEM claim 1 , DR3 or CD40.5. The immuno-responsive cell of wherein one of (b) or (e) is CD28 and the other is 4-1BB or OX40.6. The immuno-responsive cell of wherein (b) is CD28.7. The immuno-responsive cell of wherein (e) is 4-1BB or CD27.8. The immuno-responsive cell of wherein the transmembrane domains of (c) and (f) are selected from CD8α and CD28 transmembrane domains.9. The immuno-responsive cell of wherein the first and second epitopes are associated with the same receptor or antigen.10. The immuno-responsive cell of which co-expresses a chimeric cytokine receptor.11. The immuno-responsive cell of wherein the chimeric cytokine receptor is 4αβ.12. The immuno-responsive cell of wherein at least one of binding element (d) or binding element (g) is a ligand for an ErbB dimer claim 1 , a receptor for colony stimulating factor-1 (CSF-1R) or an αβintegrin-specific binding agent.13. The immuno-responsive cell of wherein binding element (d) comprises CSF-1 and ...

COMPOSITIONS AND METHODS FOR USE OF RECOMBINANT T CELL RECEPTORS FOR DIRECT RECOGNITION OF TUMOR ANTIGEN

Provided are compositions and methods for prophylaxis and/or therapy of a variety of cancers which express a NY-ESO-1 antigen. Included are recombinant T cell receptors (TCRs), polynucleotides encoding them, expression vectors that include the polynucleotides, and cells into which the polynucleotides have been introduced to produce modified cells, including CD4 T cells, CD8 T cells, natural killer T cells, γδ T cells, and progenitor cells, such as haematopoietic stem cells. The modified cells are capable of direct recognition of a cancer cell expressing a NY-ESO-1 antigen by human leukocyte antigen (HLA) class II-restricted binding of the TCR to the NY-ESO-1 antigen expressed by the cancer cell without presentation of the antigen by antigen presenting cells. In embodiments, the NY-ESO-1 antigen is displayed by the tumor cells. Also included is a method for prophylaxis and/or therapy of cancer by administering modified cells that express a recombinant TCR. Methods for making expression vectors and/or cells which express a recombinant TCR and identifying TCRs to make the expression vectors are also included. 1. A modified human hematopoietic stem cell comprising a recombinant polynucleotide encoding a T cell receptor (TCR) , wherein the recombinant polynucleotide encodes a TCR alpha chain having the sequence of SEQ ID NO:3 and a TCR beta chain having the sequence of SEQ ID NO:4 , or wherein the recombinant polynucleotide encodes a TCR alpha chain having the sequence of SEQ ID NO:11 and a TCR beta chain having the sequence of SEQ ID NO:12.2. The modified cell of claim 1 , comprising the recombinant polynucleotide that encodes the TCR alpha chain having the sequence of SEQ ID NO:3 and the TCR beta chain having the sequence of SEQ ID NO:4.3. The modified cell of claim 1 , comprising the recombinant polynucleotide that encodes the TCR alpha chain having the sequence SEQ ID NO:11 and the TCR beta chain having the sequence of SEQ ID NO:12.4. A method for prophylaxis and/or ...

T CELL RECEPTORS SPECIFIC FOR THE NY-ESO-1 TUMOR ANTIGEN-HLA-A*02 COMPLEX

The present invention relates to T cell receptors (TCRs) which bind the HLA-A*02 restricted peptide SLLMWITQC derived from the cancer antigen NY-ESO-1. Said TCRs may comprise mutations within the alpha and/or beta variable domains relative to a native NY-ESO-1 TCR. The TCRs of the invention are particularly suitable for use as novel immunotherapeutic reagents for the treatment of malignant disease. 1. A T cell receptor (TCR) having the property of binding to SLLMWITQC (SEQ ID NO: 1) HLA-A*02 complex and comprising a TCR alpha chain variable domain and/or a TCR beta chain variable domain ,the alpha chain variable domain comprises an amino acid sequence that has at least 90% identity, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity, to amino acids 1-117 of SEQ ID NO: 2, and/orthe beta chain variable domain comprises an amino acid sequence that has at least 90% identity, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity, to amino acids 1-115 of SEQ ID NO: 3.2. A TCR that binds to a SLLMWITQC (SEQ ID NO: 1) HLA-A*02 complex with an affinity greater than 50 μM , wherein: the alpha chain CDRs 1 , 2 and 3 comprise SEQ ID NO: 41 , 42 and 43 respectively , and/or the beta chain CDRs 1 , 2 and 3 comprise SEQ ID NO: 44 , 45 and 46 respectively; and/or at least one of the CDRs contains one or more conservative substitutions with respect to SEQ ID NO: 41 to 46; and/or at least one of the CDRs contains up to three tolerated substitutions with respect to SEQ ID NO: 41 to 46.5. A TCR as claimed in any one of to wherein the alpha chain variable domain has at least one of the following groups of mutationsGroup 1: I51L, T52G, G53D, D54S, N55AGroup 2: I51L, T52G, G53D, D54S, N55A, N97DGroup 3: I51L, T52G, G53D, D54S, N55A, N97RGroup 4: I96S, N97D, S98Q, G99HGroup 5: D95S, I96S, N97R, S98Q, G99HGroup 6: I51L, G53Dand/or the beta chain variable domain has at least one of the following groups of mutationsGroup 1: N50W, Q51T, S53GGroup 2: ...

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST VARIOUS TUMORS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has cancer , comprising administering to said patient a population of activated T cells that selectively recognize cells that aberrantly express a peptide consisting of the amino acid sequence selected from the group consisting of SEQ ID NO: 1 , from SEQ ID NO: 3 to SEQ ID NO: 10 , SEQ ID NO: 12 , SEQ ID NO: 13 , from SEQ ID NO: 15 to SEQ ID NO: 23 , from SEQ ID NO: 26 to SEQ ID NO: 42 , from SEQ ID NO: 44 to SEQ ID NO: 83 , from SEQ ID NO: 85 to SEQ ID NO: 116 , from SEQ ID NO: 118 to SEQ ID NO: 156 , from SEQ ID NO: 158 to SEQ ID NO: 232 , from SEQ ID NO: 234 to SEQ ID NO: 242 , SEQ ID NO: 244 , from SEQ ID NO: 247 to SEQ ID NO: 252 , from SEQ ID NO: 254 to SEQ ID NO: 263 , and from SEQ ID NO: 265 to SEQ ID NO: 288;wherein said cancer is selected from the group consisting of hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), glioblastoma (GB), gastric cancer (GC), esophageal cancer, non-small cell lung cancer (NSCLC), pancreatic cancer (PC), renal cell carcinoma (RCC), benign prostate hyperplasia (BPH), prostate cancer (PCA), ovarian cancer (OC), melanoma, breast cancer (BRCA), chronic lymphocytic leukemia (CLL), Merkel cell carcinoma (MCC), small cell lung cancer (SCLC), Non-Hodgkin ...

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST ESOPHAGEAL CANCER AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has cancer , comprising administering to said patient a population of activated T cells that selectively recognize cells , which present a peptide consisting of the amino acid sequence of SEQ ID NO: 67 ,wherein the activated T cells are cytotoxic T cells produced by contacting T cells with an antigen presenting cell that expresses the peptide in a complex with an MHC molecule on the surface of the antigen presenting cell, for a period of time sufficient to activate said T cell, andwherein said cancer is selected from the group consisting of esophageal cancer, lung cancer, urinary bladder cancer, ovarian cancer, melanoma, uterine cancer, hepatocellular cancer, renal cell cancer, brain cancer, colorectal cancer, breast cancer, gastric cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, prostate cancer, and leukemia.2. The method of claim 1 , wherein the T cells are autologous to the patient.3. The method of claim 1 , wherein the T cells are obtained from a healthy donor.4. The method of claim 1 , wherein the T cells are obtained from tumor infiltrating lymphocytes or peripheral blood mononuclear cells.5. The method of claim 1 , wherein the activated T cells are expanded in vitro.6. The ...

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST ESOPHAGEAL CANCER AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has cancer , comprising administering to said patient a population of activated T cells that selectively recognize cells which present a peptide consisting of the amino acid sequence of SEQ ID NO: 32 ,wherein the activated T cells are cytotoxic T cells produced by contacting T cells with an antigen presenting cell that expresses the peptide in a complex with an MHC molecule on the surface of the antigen presenting cell, andwherein said cancer is selected from the group consisting of esophageal cancer, lung cancer, urinary bladder cancer, ovarian cancer, melanoma, uterine cancer, hepatocellular cancer, renal cell cancer, brain cancer, colorectal cancer, breast cancer, gastric cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, prostate cancer, and leukemia.2. The method of claim 1 , wherein the T cells are autologous to the patient.3. The method of claim 1 , wherein the T cells are obtained from a healthy donor.4. The method of claim 1 , wherein the T cells are obtained from tumor infiltrating lymphocytes or peripheral blood mononuclear cells.5. The method of claim 1 , wherein the activated T cells are expanded in vitro.6. The method of claim 1 , wherein the MHC molecule is an MHC class I ...

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST LUNG CANCER, INCLUDING NSCLC, SCLC AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has lung cancer , comprising administering to the patient a population of activated T cells that selectively recognize cells that present a peptide consisting of the amino acid sequence of SEIEQEIGSL (SEQ ID NO: 478).2. The method of claim 1 , wherein the T cells are autologous to the patient.3. The method of claim 1 , wherein the T cells are obtained from a healthy donor.4. The method of claim 1 , wherein the T cells are obtained from tumor infiltrating lymphocytes or peripheral blood mononuclear cells.5. The method of claim 1 , wherein the activated T cells are expanded in vitro.6. The method of claim 1 , wherein the population of activated T cells are administered in the form of a composition.7. The method of claim 6 , wherein the composition further comprises an adjuvant.8. The method of claim 7 , wherein the adjuvant is selected from anti-CD40 antibody claim 7 , imiquimod claim 7 , resiquimod claim 7 , GM-CSF claim 7 , cyclophosphamide claim 7 , sunitinib claim 7 , bevacizumab claim 7 , interferon-alpha claim 7 , interferon-beta claim 7 , CpG oligonucleotides and derivatives claim 7 , poly-(I:C) and derivatives claim 7 , RNA claim 7 , sildenafil claim 7 , particulate formulations with poly(lactide ...

Novel t cell receptors and immune therapy using the same

The present invention pertains to antigen recognizing constructs against tumor associated antigens (TAA), in particular the TAA Serine protease inhibitor Kazal-type 2 (SPINK2). The invention in particular provides novel T cell receptor (TCR) based molecules which are selective and specific for the tumor expressed antigen of the invention. The TCR of the invention, and SPINK2 binding fragments derived therefrom, are of use for the diagnosis, treatment and prevention of SPINK2 expressing cancerous diseases. Further provided are nucleic acids encoding the antigen recognizing constructs of the invention, vectors comprising these nucleic acids, recombinant cells expressing the antigen recognizing constructs and pharmaceutical compositions comprising the compounds of the invention.

TRANSGENE GENETIC TAGS AND METHODS OF USE

The present invention provides genetic tags operably linked to transgenes. The expression of the genetic tag allows identification, detection, selection, and ablation of cells expressing the transgene and the genetic tag. In some alternatives the genetically modified host cell comprises a transgene comprising a polynucleotide coding for a chimeric antigen receptor comprising a ligand binding domain, a polynucleotide comprising a spacer region, a polynucleotide comprising a transmembrane domain, and a polynucleotide comprising an intracellular signaling domain and a polynucleotide coding for a genetic tag. In some alternatives the genetically modified host cell comprises a transgene comprising a polynucleotide coding for a chimeric antigen receptor comprising a ligand binding domain, a polynucleotide comprising a spacer region, a polynucleotide comprising a transmembrane domain, and a polynucleotide comprising an intracellular signaling domain and a polynucleotide coding for a genetic tag, and wherein the polypeptide further comprises a flexible linker comprising amino acids GGGSGGGS (SEQ ID NO:45). Pharmaceutical formulations produced by the method, and methods of using the same, are also described. 148.-. (canceled)49. A nucleic acid comprising a first polynucleotide encoding a fusion protein , wherein the fusion protein comprises:an extracellular domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:18;a spacer, wherein the spacer is selected from the group consisting of a CD28 hinge domain, an IgG4 hinge domain, and a polypeptide comprising the amino acid sequence of SEQ ID NO:45; anda transmembrane domain, wherein the transmembrane domain is linked to the extracellular domain via the spacer.50. The nucleic acid of claim 49 , wherein the spacer comprises the amino acid sequence of SEQ ID NO:45.51. The nucleic acid of claim 49 , wherein the spacer comprises the IgG4 hinge domain.52. The nucleic acid of claim 51 , wherein the ...

NOVEL HUMANIZED ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR, ITS NUCELIC ACID SEQUENCE AND ITS PREPARATION

The present invention relates to novel humanized anti-CD19 chimeric antigen receptor containing an optimized anti-CD19 binding domain effective against the treatment of disease associated with expression of the Cluster of Differentiation 19 protein (CD19), and to a nucleic acid molecule encoding the humanized CAR. The invention also encompasses a process forth preparation of the CAR, composition containing the CAR, vectors containing the polynucleotide encoding the CAR and cells expressing the Carat their surface, in particular for their use in immunotherapy. 2. The nucleic acid molecule as claimed in claim 1 , which encodes a heavy chain complementary determining region 1 (HC CDR1) of SEQ ID No: 6 claim 1 , a heavy chain complementary determining region 2 (HC CDR2) of SEQ ID No: 8 or SEQ ID No. 9 claim 1 , a heavy chain complementary determining region 3 (HC CDR3) of SEQ ID No: 11 and a light chain complementary determining region 1 (LC CDR1) of SEQ ID No: 14 claim 1 , a light chain complementary determining region 2 (LC CDR2) of SEQ ID No: 16 claim 1 , and a light chain complementary determining region 3 (LC CDR3) of SEQ ID No: 18.3. The nucleic acid molecule as claimed in any of the preceding claims claim 1 , which encodes a heavy chain variable region (HCVR) selected from SEQ ID No: 1 claim 1 , SEQ ID No: 2 & SEQ ID No. 58 and a light chain variable region (LCVR) of SEQ ID No: 3.4. The nucleic acid molecule as claimed in claim 1 , which comprises a nucleic acid sequences encoding the HCVR and the LCVR claim 1 , wherein the nucleic acid sequence encoding the HCVR comprises the nucleotide sequence selected from SEQ ID No. 35 claim 1 , SEQ ID No. 36 & SEQ ID No.63 claim 1 , or nucleotide sequence with at least 95% identity thereof claim 1 , and the nucleic acid sequence encoding the LCVR comprises the nucleotide sequence selected from SEQ ID No. 37 claim 1 , SEQ ID No. 50 and SEQ ID No. 51 claim 1 , or nucleotide sequence with at least 95% identity thereof.5. The ...

Cd33 specific chimeric antigen receptors for cancer immunotherapy

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD33 monoclonal antibody, conferring specific immunity against CD33 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia.

CD123 SPECIFIC CHIMERIC ANTIGEN RECEPTORS FOR CANCER IMMUNOTHERAPY

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD123 monoclonal antibody, conferring specific immunity against CD123 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia. 1. A chimeric antigen receptor (CAR) comprising:{'sub': H', 'L, 'an extracellular ligand binding domain comprising a heavy chain variable region (V) and a light chain variable region (V) from a monoclonal anti-CD123 antibody;'}an FcγRIIIα, CD8α, or IgG1 hinge;a CD8α or 4-1BB transmembrane domain; anda cytoplasmic domain comprising a CD3-ζ signaling domain and a co-stimulatory domain from 4-1BB2. The CAR of wherein the CAR has at least 80% sequence identity with SEQ ID NO. 42 claim 1 , SEQ ID NO. 44 claim 1 , or SEQ ID NO. 46.3. The CAR of claim 1 , wherein the Vregion comprises the following CDR sequences:SEQ ID NO. 67, SEQ ID NO. 68, and SEQ ID NO. 69.4. The CAR of claim 1 , wherein the Vregion comprises the following CDR sequences: SEQ ID NO. 70 claim 1 , SEQ ID NO. 71 claim 1 , and SEQ ID NO. 72.5. (canceled)6. The CAR of claim 1 , wherein the extracellular ligand binding domain comprises at least one of the following sequences:SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 56, SEQ ID NO. 57, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 60, SEQ ID NO. 61, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65, SEQ ID NO. 66, or a combination thereof.7. The CAR of claim 1 , comprising a CD8α hinge and a CD8α transmembrane domain.8. The CAR of claim 1 , comprising:a polypeptide having at least 80% sequence identity with a polypeptide of SEQ ID NO. 19; anda polypeptide having at least 80% sequence identity with a polypeptide of SEQ ID NO. 20.9. The CAR of claim 1 , further comprising another ...

Targeted Protein Degradation

The invention relates to a method of controlling the level of a polypeptide sequence comprising administering a polypeptide sequence fused to a ubiquitin targeting protein which comprises a minimal degron structural motif. In particular, the polypeptide sequence comprises a chimeric antigen receptor therefore the present invention is useful in methods of cell and gene therapy where the activity of the chimeric antigen receptor needs to be controlled. 1. A method of controlling the level of a polypeptide sequence comprising:a) administering a fusion protein comprising said polypeptide sequence and a ubiquitin targeting protein consisting of less than 135 amino acids in length which comprises the hairpin motif of a cereblon binding site, andb) controlling the level of the polypeptide sequence by administering a compound which mediates binding of the ubiquitin targeting protein and cereblon.2. The method of claim 1 , wherein the hairpin motif comprises a sequence selected from the group consisting of: SEQ ID NOs: 2-5 or a functional variant thereof claim 1 , wherein one or two amino acids may be substituted claim 1 , added or deleted except for the GLY residue present in each amino acid sequence.3. The method of claim 1 , wherein the hairpin motif comprises a sequence selected from the group consisting of: SEQ ID NOs: 2-5.4. The method of claim 1 , wherein the ubiquitin targeting protein is a polypeptide sequence consisting of less than 100 amino acids in length.5. The method of claim 1 , wherein the ubiquitin targeting protein comprises a lysine residue which acts as a ubiquitination site.6. The method of claim 1 , wherein the ubiquitin targeting protein comprises a sequence selected from the group consisting of: SEQ ID NOs: 6-14 and 27.7. The method of claim 1 , wherein the polypeptide sequence controlled by administering a compound which mediates binding of the ubiquitin targeting protein and cereblon is a transmembrane protein.8. The method of claim 1 , wherein the ...

RESTIMULATION OF CRYOPRESERVED TUMOR INFILTRATING LYMPHOCYTES

The present disclosure provides methods for re-stimulating TIL populations that lead to improved phenotype and increased metabolic health of the TILs and provides methods of assaying for TIL populations to determine suitability for more efficacious infusion after re-stimulation. 1. A population of expanded tumor infiltrating lymphocytes (TILs) , wherein the population of expanded TILs is a third population of TILs obtainable by a method comprising:(a) performing a first expansion by (i) thawing cryopreserved dissociated tumor materials comprising a first population of TILs obtained from a tumor that was resected from a subject, and (ii) culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs;(b) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, and wherein the second expansion is performed for about 7 to 14 days in order to obtain the third population of TILs; and(c) harvesting the third population of TILs obtained from step (b).2. The population of expanded TILs according to claim 1 , wherein the method further comprises a step (d) of transferring the harvested third population of TILs from step (c) into an infusion bag.3. The population of expanded TILs according to claim 2 , wherein the method further comprises a step (e) of cryopreserving the infusion bag comprising the harvested TIL population from step (d) using a cryopreservation process.4. The population of expanded TILs according to claim 1 , wherein the dissociated tumor materials comprise a tumor digest.5. The population of expanded TILs according to claim 1 , wherein obtaining the dissociated tumor materials comprises fragmenting the tumor resected from the subject into one or more tumor fragments.6. The ...

IMMUNOTHERAPY WITH B*08 RESTRICTED PEPTIDES AND COMBINATION OF PEPTIDES AGAINST CANCERS AND RELATED METHODS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of treating a patient who has cancer , comprising administering to said patient a population of activated T cells that kill cancer cells that present a peptide consisting of the amino acid sequence of YVYANHFTEA (SEQ ID NO: 291) , wherein the cancer is breast cancer , cholangiocellular carcinoma , colorectal cancer , gallbladder cancer , gastric cancer , gastro-esophageal junction cancer , hepatocellular carcinoma , head and neck squamous cell carcinoma , melanoma , non-Hodgkin lymphoma , non-small cell lung cancer , ovarian cancer , esophageal cancer , pancreatic cancer , small cell lung cancer , urinary bladder carcinoma , or uterine and endometrial cancer.2. The method of claim 1 , wherein the activated T cells are cytotoxic T cells produced by contacting T cells with an antigen presenting cell that expresses the peptide in a complex with an MHC class I molecule on the surface of the antigen presenting cell claim 1 , for a period of time sufficient to activate said T cell.3. The method of claim 1 , wherein the cancer is breast cancer.4. The method of claim 1 , wherein the cancer is cholangiocellular carcinoma.5. The method of claim 1 , wherein the cancer is colorectal cancer.6. The method of claim 1 , wherein the cancer is gallbladder cancer.7. ...

USE OF CHIMERIC ANTIGEN RECEPTOR T CELLS AND NK CELL INHIBITORS FOR TREATING CANCER

Methods for improving a clinical outcome in a subject comprising administering to a subject in need of the treatment a population of genetically engineered immune cells (e.g., T cells), which express a chimeric antigen receptor (CAR) and a natural killer (NK) cell inhibitor (e.g., daratumumab). The genetically engineered immune cells may comprise a disrupted TRAC gene, a disrupted B2M gene, or both. The disclosure also features compositions for use in the methods. 1. A method for treating cancer , the method comprising administering to a human cancer patient:(a) an effective amount of an NK cell inhibitor; and(b) an effective amount of a population of engineered human T cells expressing a CAR (CAR T cells), wherein the engineered human CAR T cells comprise disrupted MHC class I, and wherein the CAR comprises an ectodomain that comprises an antigen-binding fragment, which binds a tumor antigen.2. The method of claim 1 , wherein the engineered human CAR T cells comprise a disrupted beta-2-microglobulin (β2M) gene.3. The method of claim 1 , wherein the engineered human CAR T cells comprise:(i) a disrupted T cell receptor alpha chain constant region (TRAC) gene;(ii) a disrupted β2M gene; and(iii) a nucleic acid encoding the CAR.4. The method of claim 3 , wherein the nucleic acid encoding the CAR is inserted in the disrupted TRAC gene.5. The method of claim 1 , wherein the tumor antigen is CD19 claim 1 , CD33 claim 1 , CD70 or BCMA.6. The method of claim 1 , wherein the NK cell inhibitor is an antibody that specifically binds CD38.7. The method of claim 6 , wherein the antibody is daratumumab claim 6 , SAR650984 claim 6 , or MOR202 claim 6 , or an antigen-binding fragment thereof.8. The method of claim 1 , wherein the NK cell inhibitor is administered prior to administration of the population of engineered human CAR T cells.9. The method of claim 1 , wherein the method further comprises a pre-conditioning regimen prior to administration of the population of engineered ...

IMMUNOSUPPRESSIVE ANTIGEN-SPECIFIC CHIMERIC ANTIGEN RECEPTOR TREG CELLS FOR PREVENTION AND/OR TREATMENT OF AUTOIMMUNE AND ALLOIMMUNE DISORDERS

Described herein are immunoresponsive cells which are useful for their preventive and therapeutic potential against autoimmune diseases and rejections of solid organ transplants. 1. An immunoresponses cell comprising:a chimeric antigen receptor (CAR) that binds to glutamic acid decarboxylase 65 kDA (GAD65) in the cell;the CAR comprising:a) an intracellular signaling domain of a CD3ξ polypeptide and an intracellular signaling domain of CD28 hinge-transmembrane-intracellular region, andb) an extracellular polypeptide recognizing: at least a part of an amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6; or, at least one complete amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6.2. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell is selected from the group consisting of: T cells claim 1 , cytotoxic T cells claim 1 , regulatory T cells claim 1 , and combinations thereof.3. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell comprises a pancreatic beta cell-specific chimeric antigen receptor (CAR) regulatory T cell (Treg) that expresses at least one extracellular polypeptide and is capable of affecting Teff cells.4. The immunosuppressive cell of claim 1 , wherein the extracellular polypeptide is a GAD65 MAb antigen binding domain which recognizes: at least a part of an amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6; or claim 1 , at least one complete amino acid sequence selected from the amino acids having SEQ ID Nos: 1-6.5. A pharmaceutical composition comprising an effective amount of an immunoresponsive cell of and a pharmaceutically acceptable excipient.6. The pharmaceutical composition of claim 5 , wherein the immunoresponsive cell is a T cell.7. (canceled)8. A method of lengthening survival of a subject having type 1 diabetes (T1D) claim 5 , the method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'administering to the subject an ...

T CELL RECEPTORS SPECIFIC FOR MESOTHELIN AND THEIR USE IN IMMUNOTHERAPY

Binding proteins specific for Msln20-28 or Msln530-538 peptides are provided herein. Polynucleotides encoding the binding proteins, as well as compositions and recombinant host cells comprising the binding proteins or polynucleotides are also provided. The compositions and recombinant host cells may be used to treat a subject having mesothelioma, pancreatic cancer, ovarian cancer, lung cancer, a cancer wherein an Msln20-28 peptide is expressed on a tumor cell of the cancer, or a cancer wherein an Msln530-538 peptide is expressed on a tumor cell of the cancer. 1. A binding protein comprising a T cell receptor (TCR) α-chain variable domain (V) and a TCR β-chain variable domain (V) , wherein:{'sub': α', 'β, '(a) the V comprises the CDR3 amino acid sequence set forth in SEQ ID NO:39 or 37, and the V optionally comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO:101 or 99;'}{'sub': β', 'α, '(b) the V comprises the CDR3 amino acid sequence set forth in SEQ ID NO:40 or SEQ ID NO:38, and the V optionally comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO:102 or 100; and/or'}{'sub': α', 'β, '(c) the V comprises the CDR3 amino acid sequence set forth in SEQ ID NO:39 or 37, and the V comprises the CDR3 amino acid sequence set forth in SEQ ID NO:40 or 38,'}wherein the binding protein is capable of specifically binding to a mesothelin (Msln) peptide:HLA complex.2. The binding protein of claim 1 , wherein:{'sub': 'α', 'the V of (a), (b), and/or (c) comprises an amino acid sequence having at least about 85% identity to the amino acid sequence set forth in SEQ ID NO:102 or 100, provided that at least three or four of the CDRs have no change in sequence, wherein the CDRs that do have sequence changes have only up to two amino acid substitutions, up to a contiguous five amino acid deletion, or a combination thereof; and/or'}{'sub': 'β', '(ii) the V of ( ...

BAFF-R TARGETED CHIMERIC ANTIGEN RECEPTOR-MODIFIED T-CELLS AND USES THEREOF

Provided herein are T cells expressing a chimeric antigen receptor (CAR) targeted to B cell activating factor receptor (BAFF-R). The CAR targeted to BAFF-R (BAFF-R CAR) described herein includes a domain that binds BAFF-R. Methods of making and using the BAFF-R CAR are also provided. 1. A nucleic acid molecule encoding a chimeric antigen receptor, wherein the chimeric antigen receptor comprises an scFv targeted to BAFF-R; a transmembrane domain selected from: a CD4 transmembrane domain or variant thereof having 1-5 amino acid modifications, a CD8 transmembrane domain or variant thereof having 1-5 amino acid modifications, a CD28 transmembrane domain or a variant thereof having 1-5 amino acid modifications, and a CD3ξ transmembrane domain or a variant thereof having 1-5 amino acid modifications; a costimulatory domain; and CD3ξ signaling domain of a variant thereof having 1-5 amino acid modifications. This application is a continuation of U.S. application Ser. No. 16/307,443, Dec. 5, 2018, which is a National Phase application under 35 U.S.C. § 371 of International Application No. PCT/US2017/036178, filed Jun. 6, 2017, which claims priority to U.S. Provisional Application No. 62/346,324, filed Jun. 6, 2016, and U.S. Provisional Application No. 62/396,767, filed Sep. 19, 2016, which are incorporated herein by reference in their entireties.The instant application contains a Sequence Listing which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 1, 2021, is named 2021-09-01_Sequence_Listing_ST25_095058-1266729.txt and is 36,673 bytes in size.Tumor-specific T cell based immunotherapies, including therapies employing engineered T cells, have been investigated for anti-tumor treatment. B cell-activating factor receptor (BAFF-R) is one of three known receptors for BAFF, a regulator of B- and T-cell function.Provided herein are T cells expressing a chimeric antigen receptor (CAR) targeted ...

PERSONALIZED NEOANTIGEN-SPECIFIC ADOPTIVE CELL THERAPIES

Methods of genetically engineering NeoTCR Products comprising young T cells and methods of manufacturing such cell products. 1. A method of producing a population of modified young T cells , comprising: i. first and second homology arms homologous to first and second target nucleic acid sequences;', 'ii. a T cell receptor (TCR) gene sequence positioned between the first and second homology arms;, 'a) introducing via electroporation into a T cell a homologous recombination (HR) template nucleic acid sequence comprisingb) recombining the HR template nucleic acid into an endogenous TCR gene locus; andc) culturing the T cell in the presence of interleukin 2 (IL2), interleukin 7 (IL7), interleukin 15 (IL15), or any combination thereof, to thereby produce a population of modified young T cells.2. The method of claim 1 , wherein the culturing is in presence of IL7 and 11 claim 1 ,15.3. The method of claim 2 , wherein the culturing is not in presence of IL2.4. The method of claim 1 , wherein the HR template further comprises:a) a first P2A-coding sequence positioned upstream of the TCR gene sequence and a second P2A-coding sequence positioned downstream of the TCR gene sequence, wherein the first and second P2A-coding sequences are codon-diverged relative to each other;b) a sequence coding for the amino acid sequence Gly Ser Gly is positioned immediately upstream of the first and second P2A-coding sequences;c) a Furin cleavage site positioned upstream of the second P2A-coding sequence;d) a human growth hormone (HGH) signal sequence positioned between the first 2A-coding sequence and the TCR gene sequence.5. The method of claim 4 , wherein the HR template further comprises a second TCR sequence positioned between the second P2A-coding sequence and the second homology arm and a second HGH signal sequence positioned between the second 2A-coding sequence and the second TCR gene sequence.6. The method of claim 1 , wherein the first and second homology arms are each from about ...

CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY

The disclosure provides methods of treating a malignancy comprising administering an effective dose of a chimeric antigen receptor genetically modified T cell immunotherapy and methods for manufacturing such immunotherapy. Some aspects of the disclosure relate to methods of determining objective response of a patient to a T cell immunotherapy based on the levels of attributes prior to and after administration of the immunotherapy to the patient. 1. A method of increasing the efficacy and/or reducing the toxicity of immunotherapy (e.g. , T or non-T cells , TCR , CAR) , bi-specific T-cell engagers (BiTEs) , and/or immune checkpoint blockade treatment in a subject in need thereof , comprising:(i) administering to the subject a JAK/STAT inhibitor and decreasing the subject's systemic inflammatory state; and/or(ii) administering to the subject a JAK/STAT inhibitor and reducing the activity of myeloid cells, MCP-1, IL-6, and/or activated T cells in the subject,prior to, during, and/or after immunotherapy (e.g., T or non-T cells, TCR, CAR), (BiTEs), and/or immune checkpoint blockade treatment, preferably, T cell immunotherapy.2. (canceled)3. The method of claim 1 , wherein reducing myeloid cell activity claim 1 , MCP-1 claim 1 , and/or IL-6 activity comprises administering to the subject a monoclonal antibody against MCP-1 claim 1 , IL-6 claim 1 , IL-1 claim 1 , CSF1R claim 1 , GM-CSF and/or a small molecule.4. A method of treating claim 1 , preventing claim 1 , delaying claim 1 , reducing or attenuating the development or risk of a toxicity and/or for improving immunotherapy (e.g. claim 1 , T or non-T cells claim 1 , TCR claim 1 , CAR) claim 1 , bi-specific T-cell engagers (BiTEs) claim 1 , and/or immune checkpoint blockade treatment therapy efficacy in a subject in need thereof claim 1 , comprising administering to the subject a JAK/STAT inhibitor before claim 1 , after claim 1 , and/or during immunotherapy (e.g. claim 1 , T or non-T cells claim 1 , TCR claim 1 , CAR) ...

T-CELL EXPRESSING CHIMERIC RECEPTOR

Provided is a T-cell expressing a chimeric receptor, wherein the chimeric receptor specifically recognizes BCMA, and the endogenous TCR molecule and the endogenous MHC molecule are silenced. Also provided is the use of the T-cell in the preparation of a drug for treating BCMA positive tumors. 122-. (canceled)23. A T cell expressing a chimeric receptor that specifically recognizes BCMA , wherein the endogenous TCR molecule is silenced and the endogenous MHC molecule is silenced in the T cell.24. The T cell of claim 23 , wherein the “TCR molecule is silenced” refers to that the genes encoding either or both the α chain and the β chain of the TCR are silenced;preferably, the “TCR molecule is silenced” refers to that the gene encoding the α chain of the TCR is silenced (i.e., the TRAC gene);more preferably, the “TCR molecule is silenced” refers to that the gene encoding the constant region of the α chain of the TCR is silenced;further preferably, the “TCR molecule is silenced” refers to that the first exon of the gene encoding the constant region of the α chain of the TCR is silenced.25. The T cell of claim 23 , wherein the MHC molecule is an HLA molecule.26. The T cell of claim 23 , wherein the HLA molecule is selected from HLA-I and/or HLA-II claim 23 , comprising at least one of HLA-A claim 23 , HLA-B claim 23 , HLA-C claim 23 , B2M and CIITA molecules.27. The T cell of claim 26 , wherein the HLA molecule is an HLA class I molecule claim 26 , preferably the HLA molecule is a B2M molecule.28. The T cell of claim 23 , wherein gene editing technology is used to silence the endogenous TCR molecule and the endogenous MHC molecule.29. The T cell of claim 28 , wherein the gene editing technology is selected from the group consisting of: CRISPR/Cas technology claim 28 , artificial Zinc Finger Nucleases (ZFN) technology claim 28 , transcription activation-like effector activator-like effector (TALE) technology or TALE-CRISPR/Cas technology; preferably claim 28 , CRISPR/Cas ...

HIGH-AFFINITY TCR FOR AFP RECOGNITION

Provided in the present invention is a T-cell receptor (TCR) having the characteristic of binding a FMNKFIYEI-HLA A0201 complex; and the binding affinity of the TCR to the FMNKFIYEI-HLA A0201 complex is at least 5 times that of a wild-type TCR to the FMNKFIYEI-HLA A0201 complex. Further provided in the present invention is a fusion molecule of the TCR with a therapeutic agent. The TCR can be used alone or in combination with the therapeutic agent, so as to target a tumor cell presenting the FMNKFIYEI-HLA A0201 complex. 2. The TCR of claim 1 , wherein there are 1-5 mutations in the 3 CDR regions of the TCR α chain variable domain and/or 2-8 mutations in the 3 CDR regions of the TCR β chain variable domain or the mutated position in the α chain variable domain of the TCR includes position 8 and/or position 9 of CDR3α.3. The TCR of claim 1 , wherein the affinity of the TCR for FMNKFIYEI-HLA A0201 complex is at least 5 times of that of the wild type TCR.45-. (canceled)7. The TCR of claim 1 , wherein the TCR comprises a TCR α chain variable domain and a TCR β chain variable domain claim 1 , and said TCR α chain variable domain comprises CDR1α claim 1 , CDR2α and CDR3α claim 1 , wherein the amino acid sequence of CDR1α is TSINN; and/or the amino acid sequence of CDR2α is IRSNERE.819-. (canceled)20. The TCR of claim 1 , wherein the TCR comprises a TCR α chain variable domain and a TCR β chain variable domain claim 1 , and said TCR β chain variable domain comprises CDR1β claim 1 , CDR2β and CDR3β claim 1 , wherein the amino acid sequence of CDR2β is selected from the group consisting of YYNGEE and LYAGYE claim 1 , and/or the amino acid sequence of CDR3β is selected from the group consisting of ASRGIGDAGELF claim 1 , ASRGVGDAEELF claim 1 , ASRGVGDADELF claim 1 , ASRGLGDAEELF claim 1 , ASRGVGDSEELF claim 1 , ASRGVGDGEELF claim 1 , ASRGVGDANELF and ASRGVGDSDELF claim 1 , and/or the amino acid sequence of CDR1β is selected from the group consisting of SGDLS claim 1 , PGDIP ...

TUMOR-SPECIFIC ANTI-EGFR ANTIBODY AND APPLICATION THEREOF

The present invention provides a tumor-specific anti-EGFR antibody and application thereof. The antibody can be used for preparing targeted antitumor drugs and tumor diagnosis drugs. 136-. (canceled)37. A multi-functional immunoconjugate , comprising:an antibody; anda functional molecule linked thereto; and the functional molecule is selected from a group consisting of a molecule that targets a tumor surface marker, a tumor-suppressing molecule, a molecule that targets a surface marker of an immune cell, a detectable label;wherein the antibody specifically recognizing EGFRvIII expressed or EGFR overexpressed by tumor cells, wherein the antibody comprises a light chain variable region and a heavy chain variable region, andCDR1 of the light chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NO: 41, SEQ ID NO: 47, SEQ ID NO: 55;CDR2 of the light chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NO: 42, SEQ ID NO: 53;CDR3 of the light chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NO: 43, SEQ ID NO: 48, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 57;CDR1 of the heavy chain variable region has the amino acid sequence of SEQ ID NO: 44;CDR2 of the heavy chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 52;CDR3 of the heavy chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NO: 46, SEQ ID NO: 50.38. The multi-functional immunoconjugate of claim 37 , wherein the molecule that targets the tumor surface marker is an antibody or ligand that binds to a tumor surface marker; orthe tumor-suppressing molecule is an anti-tumor cytokine or an anti-tumor toxin; preferably, the cytokines include but are not limited to: IL-12, IL-15, IFN-beta, TNF-alpha.39. The multi-functional immunoconjugate of claim 37 , wherein the detectable ...

HUMANIZED BCMA ANTIBODY AND BCMA-CAR-T CELLS

The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising Vhaving the amino acid sequence of SEQ ID NO: 3 and Vhaving the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. This humanized BCMA-CAR-T cells have specific killing activity against BCMA-positive tumor cells. 127-. (canceled)28. A therapeutic agent for inhibiting growth of tumors , the agent comprising immune cells expressing an anti-BCMA chimeric antigen receptor (CAR) having an anti-BCMA single-chain variable fragment (scFv) comprising:{'sub': H', 'L, 'a. a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region V) comprising the amino acid sequence of SEQ ID NO: 5;'}b. a transmembrane domain;c. a co-stimulatory domain; andd. an activating domain;and further comprising an excipient.291. The therapeutic agent of claim , wherein the immune cells are selected from T cells , NK cells , macrophages , and hematopoietic cells.301. The therapeutic agent of claim , further comprising one or more of a checkpoint inhibitor , a targeted therapy , and a small molecule tumor inhibitor.311. The therapeutic agent of claim , further comprising a safety switch agent selected from t-EGFR , Rituximab-CD34-Rituximab (RQR) , and inducible caspase-9.321. The therapeutic agent of claim , wherein the transmembrane domain of the CAR is selected from the group consisting of a T cell receptor α chain , a T cell receptor β chain , a CD3 zeta chain , a CD28 , a CD3ε , a CD45 , a CD4 , a CD5 , a CD8 , a CD9 , a CD16 , a CD22 , a CD33 , a CD37 , a CD64 , a CD80 , a CD86 , a CD134 , a CD137 , an ICOS , a CD154 , and a GITR.331. The therapeutic ...

METHODS OF IDENTIFYING IMMUNOMODULATORY GENES

Disclosed herein are methods for identifying immunomodulatory genes. In some embodiments, the method comprises of screening a candidate gene comprising: a) expressing an exogenous cellular receptor, or a functional portion thereof, in a plurality of immune cells; b) introducing into said plurality of immune cells: i. a guiding polynucleic acid, or a nucleic acid encoding said guiding polynucleic acid, wherein said guiding polynucleic acid targets said candidate gene; and ii. an exogenous nuclease, or a nucleic acid encoding said exogenous nuclease; thereby generating a plurality of engineered immune cells comprising a genomic disruption in said candidate gene; c) contacting said plurality of engineered immune cells with a plurality of cells expressing a cognate antigen of said exogenous cellular receptor or a functional portion thereof, thereby performing an in vitro assay; and d) determining a readout of said in vitro assay. 1. A method of screening a plurality of single candidate genes , said method comprising:a. expressing an exogenous cellular receptor, or a functional fragment thereof, in a plurality of separate populations of immune cells, wherein each population comprises a plurality of immune cells; i. a guide nucleic acid that binds a portion of a single candidate gene, wherein said single candidate gene is different for each of said separate populations of immune cells; and', 'ii. an exogenous nuclease, or a nucleic acid encoding said exogenous nuclease;, 'b. introducing into each of said separate populations of immune cells a CRISPR system that comprisesthereby generating a plurality of separate populations of engineered immune cells that comprise a genomic disruption in said single candidate gene, wherein said genomic disruption that suppresses expression of said single candidate gene;c. performing an in vitro assay that comprises contacting said plurality of engineered immune cells with a plurality of cells expressing a cognate antigen of said exogenous ...

CHIMERIC ANTIGEN RECEPTOR TARGETING OF TUMOR ENDOTHELIUM

Disclosed are methods, protocols, and compositions of matter related to utilization of chimeric antigen receptor (CAR) expressing cells for the targeting of tumor endothelium utilizing chimeric antigen receptor expressing stem cells. In one embodiment tumor endothelium specific antigens are utilized as targets of the antigen binding domain of a CAR, which is attached to an extracellular hinge domain, a domain that transverses the T cell membrane and an intracellular domain associated with T cell signaling. Suitable antigens for the practice of the invention include TEM-1, ROBO-4, surviving, and FasL. In other aspects of the invention antigens are identified through serological analysis of recombinant cDNA expression libraries (SEREX) using plasma from a patient immunized with placental endothelial cells. 1. A method of immunologically inhibiting neoangiogenesis comprising:a) obtaining a cell population from peripheral blood;b) transfecting said population with a chimeric antigen receptor (CAR); andc) introducing said transfected cell population into said patient.2. The method of claim 1 , wherein said blood cell population is selected from a group comprising:a) peripheral blood mononuclear cells;b) CD4 T cells;c) CD8 T cells;d) NK cells;e) NKT cells; andf) gamma delta T cells.3. The method of claim 2 , wherein said CD4 T cells are isolated by means of magnetic separation prior to transfection with CAR.4. The method of claim 2 , wherein said CD8 T cells are isolated by means of magnetic separation prior to transfection with CAR.5. The method of claim 1 , wherein said CAR is comprised of:a) an antigen binding domain;b) a transmembrane domain;c) a costimulatory signaling region; andd) a CD3 zeta signaling domain.6. The method of claim 5 , wherein said CD3 zeta chain is resistant to cleavage by caspase 3 by means of amino acid substitution.7. The method of claim 5 , wherein the antigen binding domain is an antibody or an antigen-binding fragment thereof.8. The method of ...

CAR-T CELLS TARGETING IL-1RAP AND THEIR USE

The present invention is relative to an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antibody or antibody fragment which includes a anti-IL-1RAP binding domain, polypeptides encoded by this nucleic acid molecule, isolated chimeric antigen receptor (CAR) molecule comprising such an antibody or antibody fragment, a vector comprising a nucleic acid molecule encoding a CAR, as well as a T cell comprising this vector. The present invention is also relative to the use of this T cell (autologous or allogeneic) expressing a CAR molecule to treat a proliferative disease in a mammal. 1. An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) , wherein the CAR comprises an antibody or antibody fragment which includes an anti-IL-1RAP binding domain , a transmembrane domain , and an intracellular signaling domain comprising at least a stimulatory domain , and wherein said anti-IL-1RAP binding domain comprises:(i) a light chain comprising a complementary determining region 1 (CDR1) having at least 80% identity with the amino acid sequence SEQ ID NO: 6, a complementary determining region 2 (CDR2) having at least 80% identity with the amino acid sequence SEQ ID NO: 7 and a complementary determining region 3 (CDR3) having at least 80% identity with the amino acid sequence SEQ ID NO: 8, and(ii) a heavy chain comprising a complementary determining region 1 (CDR1) having at least 80% identity with the amino acid sequence SEQ ID NO: 12, a complementary determining region 2 (CDR2) having at least 80% identity with the amino acid sequence SEQ ID NO: 13 and a complementary determining region 3 (CDR3) having at least 80% identity with the amino acid sequence SEQ ID NO: 14.2. The isolated nucleic acid molecule of claim 1 , wherein the IL-1RAP binding domain is selected from the group consisting of an antibody claim 1 , a Fv claim 1 , a scFv claim 1 , a Fab claim 1 , or another antibody fragment claim 1 , ...

METHODS OF MAKING AND USING GUIDANCE AND NAVIGATION CONTROL PROTEINS

The application provides methods for generating a therapeutic composition. The method includes the steps of providing a cell material comprising a cytotoxic cell, incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell, and formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic composition is substantially free of exogenous viral and non-viral DNA or RNA. The first GNC protein comprises a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor. The first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the first cytotoxic cell receptor. 1. A method for generating a therapeutic composition , comprisingproviding a cell material comprising a cytotoxic cell, wherein the first GNC protein comprising a first cytotoxic binding moiety and a first cancer targeting moiety, wherein the first cytotoxic binding moiety has a specificity to a first cytotoxic cell receptor and is configured to activate the first cytotoxic cell through the binding with the first cytotoxic cell receptor, and wherein the first cancer targeting moiety has a specificity to a first cancer cell receptor, and', 'wherein the first therapeutic cell comprises the first GNC protein bound to the cytotoxic cell through the binding interaction with the first cytotoxic cell receptor, and, 'incubating the cell material with a first GNC protein to provide an activated cell composition, wherein the activated cell composition comprises a first therapeutic cell,'}formulating the activated cell composition to provide a therapeutic composition, wherein the therapeutic ...

NOVEL IMMUNOTHERAPY AGAINST SEVERAL TUMORS OF THE BLOOD, SUCH AS ACUTE MYELOID LEUKEMIA (AML)

The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to several novel peptide sequences and their variants derived from HLA class I and HLA class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.

Expression of Chimeric Polypeptide with Variable Lymphocyte Receptors on Immune Cells and Uses for Treating Cancer

This disclosure relates to recombinant cellular expression of chimeric proteins with peptide sequences derived from lymphocyte receptors and uses for treating cancer. In certain embodiments, the disclosure relates to a recombinant vector comprising a nucleic acid that encodes a chimeric protein with a segment with a targeting moiety based on a variable lymphocyte receptor (VLR) capable of binding a tumor associated antigen and a segment with a T cell signal transduction subunit. In certain embodiments, the recombinant vectors are used in immune based cancer treatments. 1. A recombinant vector comprising a nucleic acid that encodes a chimeric polypeptide comprising a targeting sequence of variable lymphocyte receptor domain or variant thereof , a transmembrane domain , a T cell costimulatory molecule domain , and a signal-transduction component of a T-cell antigen receptor domain.2. The recombinant vector of claim 1 , wherein the variable lymphocyte receptor domain contains a polypeptide sequence of less than 250 amino acids and 4 or 5 or more segments having SEQ ID NO: 1 (XXLXLXX) wherein X may be any amino acid and L may be claim 1 , individually and independently at each occurrence claim 1 , leucine or isoleucine or one L (leucine or isoleucine) may be substituted with any amino acid.3. The recombinant vector of claim 2 , wherein the variable lymphocyte receptor has a sequence VXCXXXXLXSVPAXIPTTTXXLXXXXNXITKXXPGVFDXLXXLXXXXL XXNXLXXXPXGXFD (SEQ ID NO: 2) wherein X may be any amino acid.4. The recombinant vector of claim 2 , wherein the variable lymphocyte receptor has SEQ ID NO: 4 claim 2 , 6 claim 2 , 8 claim 2 , 10 claim 2 , or a sequence with greater than 95% identity thereto.5. The recombinant vector of claim 2 , wherein the nucleic acid has SEQ ID NO: 3 claim 2 , 5 claim 2 , 7 claim 2 , 9 claim 2 , or a sequence with greater than 95% identity thereto.6. The recombinant vector of claim 1 , wherein the costimulatory molecule is selected from CD28 claim 1 , CD80 ...

TUMOR INFILTRATING LYMPHOCYTES AND METHODS OF THERAPY

Genetically modified compositions, such as non-viral vectors and tumor infiltrating lymphocytes, for the treatment of gastrointestinal cancer are disclosed. Disclosed are methods of utilizing a CRISPR system to generate genetically modified compositions. Also disclosed are the methods of making and using the genetically modified compositions for the treatment of gastrointestinal cancer. 1. A method of treatment , comprising administering to a subject in need thereof:a) a preparative regime that comprises administration of at least one immunosuppressant to said subject in an amount sufficient to reduce an immune response in said subject;b) a pharmaceutical composition that comprises an antifungal agent in an amount sufficient to inhibit a fungal infection in said subject; andc) a pharmaceutical composition that comprises a plurality of tumor infiltrating lymphocytes (TILs) that comprise a disruption of at least a portion of a cytokine inducible SH2-containing protein (CISH) gene.2. The method of claim 1 , further comprising administering a pharmaceutical composition that comprises an antibiotic in an amount sufficient to inhibit a bacterial infection in said subject.34-. (canceled)5. A method of treatment claim 1 , comprising administering to a subject in need thereof:a) a pharmaceutical composition that comprises cyclophosphamide and fludarabine in an amount sufficient to reduce an immune response in said subject;b) a pharmaceutical composition that comprises fluconazole in an amount sufficient to inhibit a fungal infection in said subject; andc) a pharmaceutical composition that comprises a plurality of tumor infiltrating lymphocytes (TILs) that comprise a disruption of at least a portion of a cytokine inducible SH2-containing protein (CISH) gene.6. The method of claim 5 , further comprising administering a pharmaceutical composition that comprises trimethoprim and sulfamethoxazole in an amount sufficient to inhibit a bacterial infection in said subject.796-. ( ...

Peptides and combination of peptides for use in immunotherapy against cancers

The present description relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present description relates to the immunotherapy of cancer. The present description further relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T-cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

Antigen-specific helper t-cell receptor genes

The present invention pertains to polynucleotides that encode CDR3 in TCR-[alpha] and TCR-[beta] chain genes of CD4 + helper T-cells that are specific to WT1 helper peptides having an amino acid sequence represented by SEQ ID NO: 123. The present invention further pertains to the peptides encoded by said polynucleotides. The present invention further pertains to CD4 + T cells into which TCR genes that contain said polynucleotides have been introduced, the induction of WT1-specific cytotoxic T-lymphocytes (CTLs) using the CD4 + T-cells, the treatment of cancer, etc.

Chimeric Receptors with 4-1BB Stimulatory Signaling Domain

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use. 1. (canceled)2. A polynucleotide encoding a chimeric receptor comprising: (a) an extracellular ligand-binding domain; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3C signaling domain.3. The polynucleotide of claim 2 , wherein said 4-1BB signaling domain is a human 4-1BB signaling domain.4. The polynucleotide of claim 2 , wherein said 4-1BB signaling domain comprises amino acid residues 214-255 of SEQ ID NO:2.5. The polynucleotide of claim 2 , wherein said transmembrane domain comprises a transmembrane domain of CD8α.6. The polynucleotide of claim 2 , wherein said chimeric receptor further comprises a hinge domain.7. A vector comprising a polynucleotide encoding a chimeric receptor comprising:(a) an extracellular ligand-binding domain; (b) a transmembrane domain; and (c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3ζ signaling domain.8. The vector of claim 7 , wherein said 4-1BB signaling domain is a human 4-1BB signaling domain.9. The vector of claim 7 , wherein said 4-1BB signaling domain comprises amino acid residues 214-255 of SEQ ID NO:2.10. The vector of claim 7 , wherein said vector is an expression vector claim 7 , and wherein said polynucleotide is operably linked to at least one regulatory element in the appropriate orientation for expression.11. The vector of claim 10 , wherein said vector is a viral vector.12. The vector of claim 10 , wherein said vector is a retroviral ...

GENERATION AND USE IN ADOPTIVE IMMUNOTHERAPY OF STEM CELL-LIKE MEMORY T CELLS

Provided herein are methods of generating antigen-specific T cells for therapeutic administration to a human patient having or suspected of having a pathogen or cancer, utilizing stem cell-like memory T cells (Tcells). Also disclosed are antigen-specific T cells generated by such methods, and methods of treating a human patient using such antigen-specific T cells. 1. A method of generating a population of cells comprising antigen-specific T cells for therapeutic administration to a human patient having or suspected of having a pathogen or cancer , comprising: (a) ex vivo sensitizing a population of human blood cells to one or more antigens of the pathogen or cancer over a period of time in culture , wherein at the initiation of said period of time , the population of human blood cells contains at least 50% stem cell-like memory T cells (Tcells); and (b) cryopreserving (i) the ex vivo sensitized population of human blood cells , or (ii) cells derived therefrom that comprise antigen-specific T cells recognizing the one or more antigens of the pathogen or cancer; thereby producing said population of cells comprising antigen-specific T cells.2. (canceled)3. The method of claim 1 , wherein the period of time in culture is in the range of 9-21 days.4. The method of claim 3 , wherein the period of time in culture is in the range of 9-14 days.514-. (canceled)15. The method of claim 1 , wherein the population of cells comprising antigen-specific T cells comprises antigen-specific T cells that endogenously express a public T cell receptor (TCR) recognizing the one or more antigens.16. The method of claim 1 , wherein the population of cells comprising antigen-specific T cells comprises antigen-specific T cells that recombinantly express a public TCR recognizing the one or more antigens.17. (canceled)18. The method of claim 16 , which further comprises transducing the population of human blood cells with a nucleic acid encoding a public TCR at a time when the population of ...

IMMUNOMODULATORY FUSION PROTEINS AND USES THEREOF

The present disclosure relates to immunomodulatory fusion proteins containing an extracellular binding domain and an intracellular signaling domain, wherein binding of a target can generate a modulatory signal in a host cell, such as a T cell. The present disclosure also relates to uses of immune cells expressing such immunomodulatory fusion proteins to treat certain diseases, such as cancer or infectious 1. A fusion protein , comprising (a) an extracellular component comprised of a binding domain that specifically binds a target , (b) an intracellular component comprised of an intracellular signaling domain , and (c) a hydrophobic component connecting the extracellular and intracellular components ,wherein the extracellular portion of a complex formed by specific binding of the fusion protein to the target (fusion protein::target complex) is of a size, or spans a distance, of (i) up to about a distance between two cell membranes of an immunological synapse, (ii) up to about or substantially the same as a distance spanned by the extracellular portion of a complex between a T cell receptor (TCR) and an MHC-peptide complex specifically bound by the TCR, (iii) up to about or substantially the same as a distance spanned by the extracellular portion of a complex between a natural molecule comprising the binding domain and its cognate binding partner; (iii) less than or up to about 40 nm, 25 nm, 20 nm, 15 nm, or 14 nm; or (iv) any combination thereof; andwherein the extracellular component is or comprises a CD95 (Fas) ectodomain or a functional fragment thereof, and the intracellular component is or comprises a CD137 (4-1BB) intracellular signaling domain or a functional portion thereof2. The fusion protein according to claim 1 , wherein the fusion protein::target complex localizes to a supramolecular activation cluster (SMAC).3. The fusion protein according to or claim 1 , wherein the fusion protein::target complex localizes to a central region supramolecular activation ...

NUCLEIC ACID CONSTRUCTS FOR CO-EXPRESSION OF CHIMERIC ANTIGEN RECEPTOR AND TRANSCRIPTION FACTOR, CELLS CONTAINING AND THERAPEUTIC USE THEREOF

Nucleic acid constructs, vectors, and recombinant cells harboring the nucleic acid constructs or vectors are disclosed. The nucleic acid constructs include genes encoding a chimeric antigen receptor (CAR) and/or one or more transcription factors, optionally mutated. The transcription factors include those that mediate proinflammatory cytokine expression, e.g., T-bet, STAT1, or STAT4. Methods are disclosed of co-expression of the CAR and the transcription factor in a human or non-human immune cell, preferably human T cells. Also disclosed are methods for using these cells for immunotherapy, e.g., in treating cancer, infection, autoimmunity, allergy or inflammation diseases by the administration of a prophylactically or therapeutically effective amount of one or more of the nucleic acid constructs, vectors, and/or immune cells, e.g., human CAR-T cells, described herein. 1. A nucleic acid construct or constructs comprising (i) a nucleic acid encoding a chimeric antigen receptor (CAR) and (ii) at least one other nucleic acid encoding a transcription factor or a variant thereof , wherein (i) and (ii) are on the same or different constructs.2. The construct or constructs of claim 1 , wherein the transcription factor elicits one or more of the following effects in an immune cell containing said construct or constructs:(i) enhances the expression of said CAR by said immune cell,{'sup': +', '+, 'sub': 'H', '(ii) for an immune cell that is a CD4 T cell, promotes the development of the CD4 T cell to a T1 cell,'}{'sub': 'H', "(iii) promotes the immune cell's expression of T1 cytokines such as IL-2, IFNγ or TNFα,"}{'sub': H', 'H', 'H', 'FH, '(iv) suppresses the development of these immune cells or their progeny into other (non-T1) cells such as T2, T17, or Tcells,'}{'sub': 'H', '(v) suppresses the expression of T2 cytokines such as IL-13 by said immune cell or its progeny;'}(vi) enhances the immune cell's killing of target cells expressing the antigen bound by the CAR; and/or{' ...

Effective generation of tumor-targeted t cells derived from pluripotent stem cells

The present invention relates to the field of adoptive immunotherapy. The invention provides methods for generating phenotypically defined, functional, and/or expandable T cells from pluripotent stem cells engineered through safe genetic modifications. The engineered cells may provide one or more of: 1) targeting a specific predetermined antigen expressed on the cell surface of a target cell in an HLA independent manner, 2) enhanced survival and functional potential 3) “off-the-shelf” T cells for administration to multiple recipients, eventually across immunogenic barriers, and/or 4) cytotoxic potential and anti-tumor activity.

DIMERIZING AGENT REGULATED IMMUNORECEPTOR COMPLEXES

The present disclosure provides improved compositions for adoptive T cell therapies targeting CD33 for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith. The present disclosure also relates to adoptive T cell therapies targeting CD33 and another target antigen for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith. 1. A non-natural cell comprising:(a) a first polypeptide comprising: an FRB multimerization domain polypeptide or variant thereof; a CD8α transmembrane domain or a CD4 transmembrane domain; a CD137 co-stimulatory domain; and/or a CD3ζ primary signaling domain; and(b) a second polypeptide comprising: a binding domain that binds to CD33; an FKBP multimerization domain polypeptide or variant thereof; and a CD4 transmembrane domain or a CD8α transmembrane domain;wherein a bridging factor promotes the formation of a polypeptide complex on the non-natural cell surface with the bridging factor associated with and disposed between the multimerization domains of the first and second polypeptides.2. The non-natural cell of claim 1 , wherein the FKBP multimerization domain is FKBP12.3. The non-natural cell of or claim 1 , wherein the FRB polypeptide is FRB T2098L.4. The non-natural cell of any one of to claim 1 , wherein the bridging factor is selected from the group consisting of: AP21967 claim 1 , sirolimus claim 1 , everolimus claim 1 , novolimus claim 1 , pimecrolimus claim 1 , ridaforolimus claim 1 , tacrolimus claim 1 , temsirolimus claim 1 , umirolimus claim 1 , and zotarolimus.5. The non-natural cell of any one of to claim 1 , wherein the first polypeptide comprises a CD8α transmembrane domain; a CD137 co-stimulatory domain; and a CD3ζ primary signaling domain.6. The non-natural cell ...

Novel peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST PROSTATE CANCER AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A peptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 48 , and variant sequences thereof which are at least 88% homologous to SEQ ID No. 1 to SEQ ID No. 48 , wherein said variant binds to molecule(s) of the major histocompatibility complex (MHC) and/or induces T cells cross-reacting with said variant peptide; and a pharmaceutical acceptable salt thereof , wherein said peptide is not a full-length polypeptide.2. The peptide or variant according to claim 1 , wherein said peptide has the ability to bind to a MHC class-I or -II molecule claim 1 , and wherein said peptide claim 1 , when bound to said MHC claim 1 , is capable of being recognized by CD4 and/or CD8 T cells.3. The peptide or variant thereof according to claim 1 , wherein the amino acid sequence thereof comprises a continuous stretch of amino acids according to the group of SEQ ID No. 1 to SEQ ID No. 48.4. The peptide or variant thereof according to claim 1 , wherein said peptide or variant thereof has an overall length of from 8 to 100 claim 1 , optionally from 8 to 30 claim 1 , and optionally from 8 to 16 amino acids claim 1 , and optionally wherein the peptide consists or consists essentially of an amino acid sequence according to the group of ...

Method and compositions for cellular immunotherapy

The present invention provides nucleic acids, vectors, host cells, methods and compositions to confer and/or augment immune responses mediated by cellular immunotherapy, such as by adoptively transferring CD8+ central memory T cells or combinations of central memory T cells with CD4+ T cells that are genetically modified to express a chimeric receptor. In some alternatives the genetically modified host cell comprises a nucleic acid comprising a polynucleotide coding for a ligand binding domain, a poly nucleotide comprising a customized spacer region, a polynucleotide comprising a transmembrane domain, and a polynucleotide comprising an intracellular signaling domain. In some alternatives, the ligand binding domains binds to CD171.

ANTI-CLL1 SPECIFIC SINGLE-CHAIN CHIMERIC ANTIGEN RECEPTORS (SCCARS) FOR CANCER IMMUNOTHERAPY

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward CLL1 positive cells. The engineered immune cells endowed with such CARs are particularly suited for immunotherapy for treating cancer, in particular leukemia. 1. A CLL1 specific Chimeric Antigen Receptor (CAR) comprising at least:a first extra cellular ligand binding-domain that is specific for CLL1,a transmembrane domain, anda cytoplasmic signaling domain.2. The CLL1 specific CAR according to claim 1 , further comprising a co-stimulatory domain.3. The CLL1 specific CAR according to claim 1 , further comprising a CD28 or a 4-1BB co-stimulatory domain.4. The CLL1 specific CAR according to claim 1 , wherein said transmembrane domain is a CD8α transmembrane domain.5. The CLL1 specific CAR according to claim 1 , further comprising a hinge.6. The CLL1 specific CAR according to claim 1 , wherein said cytoplasmic signaling domain is a T-cell activating domain.7. The CLL1 specific CAR according to claim 1 , wherein said CAR is expressed as a single polypeptide.8. The CLL1 specific CAR according to claim 1 , wherein said extra cellular ligand binding-domain is from a monoclonal anti-CLL1 antibody.9. The CLL1 specific CAR according to claim 8 , wherein extra cellular ligand binding-domain comprises CDRs from Vand Vdomains of monoclonal anti-CLL1 antibody(ies).10. The CLL1 specific CAR according to claim 9 , wherein said CDRs are selected from SEQ ID NO. 109 to 190.11. The CLL1 specific CAR according to having a polypeptide structure of V1 claim 1 , V3 or V5 claim 1 , said structure comprising an extra cellular ligand binding-domain comprising Vand Vfrom a monoclonal anti-CLL1 antibody claim 1 , a hinge claim 1 , a Cd8α transmembrane domain claim 1 , a cytoplasmic domain including a CD3 zeta signaling domain and a 4-1BB co-stimulatory domain.12. The CLL1 specific CAR according to claim 11 , wherein said ...

T Cells with Increased Immunosuppression Resistance

This invention relates to the treatment of cancer in an individual by administration of a population of modified T cells that express a recombinant cAMP phosphodiesterase (PDE) or a fragment thereof and an antigen receptor which binds specifically to cancer cells in the individual. Populations of modified T cells and methods of producing populations of modified T cells are provided, along with pharmaceutical compositions and methods of treatment 1. A method of producing a population of modified T cells comprising;modifying a population of T cells obtained from a donor individual to express a cAMP phosphodiesterase (PDE) or a fragment thereof.2. A method according to wherein the T cells are modified by introducing a nucleic acid encoding the cAMP PDE or fragment into the T cells.3. A method according to wherein the nucleic acid encoding the cAMP PDE or fragment is comprised in an expression vector.4. A method according to wherein the T cells express an antigen receptor which binds specifically to cancer cells from the donor individual.5. A method according to wherein the antigen receptor is a T cell receptor (TCR).6. A method according to wherein the method further comprises modifying the population of T cells to express an antigen receptor which binds specifically to cancer cells.7. A method according to wherein the T cells are further modified by introducing a nucleic acid encoding the antigen receptor into the T cells.8. A method according to wherein the nucleic acid encoding the antigen receptor is comprised in an expression vector.9. A method according to wherein the antigen receptor is a heterologous TCR.10. A method according to wherein the TCR binds specifically to an MEW displaying a peptide fragment of a tumour antigen expressed by the cancer cells11. A method according to wherein the tumour antigen is NY-ESO-1 claim 10 , MAGE-A4 or MAGE-A10.12. A method according to wherein the antigen receptor is a chimeric antigen receptor (CAR).13. A method according to ...

Universal Killer T-Cell

The present invention relates to a modified natural killer (NK) cell and its use in personalised medicine. The modified NK cells of the present invention are non-immunogenic, meaning that they are able to be administered to any recipient subject without being rejected by the host immune system (they are “universal”). In a first embodiment the non-immunogenic NK cells are modified to express CD3 to allow a T-cell Receptor (TcR) to be expressed. In a further embodiment the non-immunogenic NK cells are further modified to express a TcR together with the CD3 co-receptor. Co-expression of CD3 with a specific TcR results in the modified NK cells showing antigen-specific cytotoxicity towards target cells. Universal NK cells can thus be targeted against specific antigens, and may thus be used in personalised medicine, particularly in the field of oncology. 1. A modified NK cell , wherein said cell is non-immunogenic and is modified to express CD3 , wherein the CD3 is not expressed as part of a chimeric receptor other than a TcR-CD3 fusion.2. The cell according to claim 1 , wherein said cell is modified to be non-immunogenic.3. The cell according to claim 1 , wherein said cell is a modified NK-92 cell.4. The cell according to claim 1 , wherein said cell is irradiated claim 1 , or wherein the proliferative capacity of the cell is otherwise reduced.5. The cell according to claim 1 , to wherein the cell is modified to disrupt or prevent expression of βmicroglobulin.6. The cell according to claim 1 , wherein said cell is further modified to express a TcR having specificity towards an antigen on a target cell.7. The cell according to claim 6 , wherein the TcR is co-receptor independent.8. The cell according to claim 6 , wherein the target cell is a cancer cell.9. The cell according to claim 6 , wherein the target cell is an infected cell.10. (canceled)11. (canceled)12. The cell of according to claim 16 , wherein the cell is administered for the treatment of cancer.13. The cell ...

Use of icos-based cars to enhance antitumor activity and car persistence

The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a genetically modified Th17 cell to express a CAR having an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.