PD-1

Классические и активирующие химерные антигенные рецепторы PD-1 как элемент мультитаргетного подхода в лечении гематологических и солидных новообразований

ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ , , ,

К.А. Левчук1, А.А. Голдаева2, Е.А. Столярова3, П.А. Матейкович4, А.Х. Валиуллина5, Э.Р. Булатов5, А.В. Петухов1, А.А. Дакс6, Н.А. Барлев6, Е.В. Байдюк6, Я.Г. Торопова1

1 ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341

2 ФГБОУ ВО «Санкт-Петербургский государственный университет», Университетская наб., д. 7/9, Санкт-Петербург, Российская Федерация, 199034

3 ООО «Лечебно-диагностический центр Международного института биологических систем им. Сергея Березина», ул. Есенина, д. 1, корп. 3, Санкт-Петербург, Российская Федерация, 194354

4 ООО «ХЕМА», ул. 4-я 8 Марта, д. 3, корп. 3, Москва, Российская Федерация, 125319

5 ФГАОУ ВО «Казанский (Приволжский) федеральный университет», ул. Кремлевская, д. 18, Казань, Российская Федерация, 420008

6 ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064

Для переписки: Ксения Александровна Левчук, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; тел.: +7(951)680-79-60; e-mail: ksenialevchuk2@gmail.com

Для цитирования: Левчук К.А., Голдаева А.А., Столярова Е.А. и др. Классические и активирующие химерные антигенные рецепторы PD-1 как элемент мультитаргетного подхода в лечении гематологических и солидных новообразований. Клиническая онкогематология. 2023;16(3):268–79.

DOI: 10.21320/2500-2139-2023-16-3-268-279

РЕФЕРАТ

Цель. Создание анти-PD-L1 CAR T-эффекторов, несущих внеклеточный домен PD-1 в качестве антигенраспознающего участка, и исследование их цитолитической активности. Функциональная оценка анти-PD-L1 CAR T-эффекторов in vitro с перспективой применения в мультитаргетной терапии опухолевых новообразований.

Материалы и методы. Конструкция химерного антигенного рецептора PD-1 была создана с помощью молекулярного клонирования антигенраспознающего участка молекулы человеческого PD-1 (аминокислоты 12–170) в экспрессионный плазмидный вектор млекопитающих с добавлением активационного и костимулирующего доменов. Первичные Т-лимфоциты мононуклеарной фракции периферической крови здорового донора получены методом экспансии комбинации моноклональных антител по поверхностным маркерам CD3/CD28. Анти-PD-L1 CAR T-эффекторы получены путем лентивирусной трансдукции генома первичных Т-лимфоцитов здорового донора. Экспрессию химерного рецептора PD-1 и эффективность трансдукции оценивали методом проточной цитофлюориметрии. Специфическую цитотоксическую активность анти-PD-L1 CAR T-эффекторов анализировали in vitro с помощью теста цитотоксичности в реальном времени (RTCA) при сокультивировании с клетками-мишенями линии HeLa_PD-L1. Содержание цитокинов IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-17A оценивали методом проточной цитофлюориметрии с использованием набора Human Th1/Th2/Th17 CBA Kit (BD, США).

Результаты. Эффективность лентивирусной трансдукции и доля анти-PD-L1 CAR T-эффекторов составили 42 %. Специфичность цитотоксического ответа анти-PD-L1 CAR T-эффекторов при низком соотношении эффектора/опухоли (1:20) верифицирована снижением клеточного индекса (КИ) при сокультивировании с HeLa_PD-L1 (КИ = 0,738) в 1,5 раза по сравнению с контролем (КИ = 1,0645). Увеличение синтеза цитокинов IL-2 (1000 пг/мл), IL-6 (438,5 пг/мл), TNF-α (44 пг/мл), IFN-γ (1034 пг/мл) при сокультивировании с таргетной линией-мишенью HeLa_PD-L1 указывает на функциональность исследуемых клеток-эффекторов.

Заключение. Нами получен и проверен in vitro химерный антигенный рецептор против PD-L1. Анти-PD-L1 CAR T-лимфоциты специфически «узнают» и способствуют цитолизу опухолевых клеток-мишеней путем высокой секреции провоспалительных цитокинов IFN-γ, TNF-α, IL-6 и IL-2. Химерный антигенный рецептор PD-1 можно модифицировать в активирующий (CSR) делецией CD3ζ-домена и использовать совместно с другими CAR без прогнозируемой неспецифической токсичности.

Ключевые слова: CAR T-клеточная терапия, PD-1, анти-PD-L1 CAR T-эффекторы, микроокружение опухоли, мультитаргетная иммунотерапия.

Получено: 8 февраля 2023 г.

Принято в печать: 3 июня 2023 г.

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Статистика Plumx русский

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Ингибиторы иммунных контрольных точек в терапии лимфом

ОБЗОРЫ , , , , ,

К.В. Лепик

НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова», ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022

Для переписки: Кирилл Викторович Лепик, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022; e-mail: lepikkv@gmail.com

Для цитирования: Лепик К.В. Ингибиторы иммунных контрольных точек в терапии лимфом. Клиническая онкогематология. 2018;11(4):303–12.

DOI: 10.21320/2500-2139-2018-11-4-303-312

РЕФЕРАТ

Рецепторы и лиганды программируемой клеточной гибели (PD-1 и PD-L1) — наиболее изученные представители семейства иммунных контрольных точек (ИКТ), представляют собой ключевой элемент регуляции иммунного ответа. Способность злокачественных клеток воздействовать на рецепторы ИКТ является одним из важнейших механизмов подавления противоопухолевого иммунитета. Создание препаратов — ингибиторов ИКТ предоставляет возможность контроля и активации иммунного ответа, открывая новые перспективы иммунотерапии злокачественных новообразований, в т. ч. лимфом. В данном обзоре освещаются биологические основы применения ингибиторов ИКТ при классической лимфоме Ходжкина и неходжкинских лимфомах, а также представлен опыт их использования в клинике. Кроме того, обозначены новые подходы к созданию комбинированных режимов с включением ИКТ.

Ключевые слова: иммунные контрольные точки (ИКТ), PD-1, PD-L1, классическая лимфома Ходжкина, неходжкинские лимфомы, ингибиторы ИКТ.

Получено: 25 марта 2018 г.

Принято в печать: 23 июля 2018 г.

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