Новые мишени в иммунотерапии рака

Burugu S, Dancsok AR, Nielsen TO. Emerging targets in cancer immunotherapy. Semin Cancer Biol. 2017 Oct 5. pii: S1044-579X(17)30182-7. doi: 10.1016/j.semcancer.2017.10.001.


Введение

Противоопухолевую иммунотерапию сейчас считают столпом противоопухолевого лечения наряду с хирургией, химио- и лучевой терапией. Ипилимумаб и ниволумаб/пембролизумаб принадлежат группе первых ингибиторов иммунных чекпоинтов (таргетирующих CTLA-4 и PD-1, соответственно) и теперь синтезированы ингибиторы второго поколения, предпочтительная терапия первой линии распространенного немелкоклеточного рака легкого и меланомы. Лечение с этими агентами может индуцировать резистентность через апрегуляцию дополнительных иммунных чекпоинтов, подчеркивая необходимость в новых противоопухолевых иммунно-активирующих агентах. Новые препараты таргетируют не только лимфоциты, ассоциированные с приобретенным иммунитетом через блокаду иммунно-ингибиторных чекпоинтов или как агонисты иммуностимулирующих путей, но также и врожденные иммунные процессы, опосредуемые макрофагами и естественными киллерными (NK) клетками, пути, широко релевантные для многих типов солидных карцином и гемобластозов (маркеры суммированы на рисунке 1). Последующие новые иммунные мишени для противораковой иммунотерапии были отобраны на основе более поздних стадий их доклинических/клинических исследований и на ограниченном количестве обзорных статей, описывающих некоторые из этих мишеней.

Фиг. 1. Обзор новых мишеней для противоопухолевой иммунотерапии. Иммунные ингибиторные взаимодействия маркированы красным, иммунные костимуляторные взаимодействия маркированы зеленым цветом.

Приобретенный иммунитет

Ингибиторные лимфоцитарные рецепторы

LAG-3

Lymphocyte Activation Gene 3 (LAG-3) — рецептор, экспрессируемый на поверхностни активированных Т клеток, маркер истощения с иммуносупрессорной активностью. Класс II главного комплекса гистосовместимости (MHC-II) является лигандом для LAG-3; дополнительные лиганды (например, L-селектин и галектин-3) также идентифицированы. Регуляторные Т клетки (Treg), экспрессирующие LAG-3, имеют повышенную супрессорную активность, тогда как цитотоксические CD8+ Т клетки, экспрессирующие LAG-3, показывают сниженные скорость пролиферации и продукцию эффекторных цитокинов в канцере и аутоиммунном диабете. Сплайсинговый вариант LAG-3, расщепляемый металлопротеиназами и секретируемый в клеточную микросреду, имеет иммунно активирующие свойства после связывания с MHC-II на антиген-представляющих клетках.

LAG-3+ опухоль-инфильтрирующие лимфоциты (TIL) описаны у пациентов с меланомой, канцером толстого кишечника, панкреаз, молочной железы, легкого, гематопоеза и головы и шеи, в сочетании с агрессивными клиническими чертами. Антитело-базисная блокада LAG-3 во множественных мышиных моделях рака восстанавливает CD8+ эффекторные Т-клетки и уменьшает популяции Treg, влияние, усиленное в сочетании с анти-PD-1. Недавнее изучение в мышиной модели метастатического рака яичника показывало, что блокада LAG-3 ведет к ап-регуляции других иммунных чекпоинтов (PD-1, CTLA-4 и TIM-3), и комбинированная терапия, таргетирующая LAG-3, PD-1 и CTLA-4 повышает уровни функциональных цитотоксических Т клеток, редуцируя Treg и супрессорные клетки миелоидного происхождения.

Множественные клинические исследования ранней фазы тестировали антагонистические LAG-3 агенты в комбинации с анти-PD-1 и/или анти-CTLA-4 терапией (Таблица 1). Ввиду активирующих свойств растворимого секретируемого LAG-3 растворимое агонистическое LAG-3 антитело (IMP321) было тестирование в распространенных солидных злокачественных опухолях как единичный агент [19] и продемонстрировало достаточную переносимость и эффективность с гарантией перехода ко II фазе.

TIM-3

Tcell Immunoglobulinand Mucindomaincontaining molecule 3 (TIM-3) является иммунно-ингибиторной молекулой, первоначально идентифицированной на CD4+ Th1 (хелперных) Т-клетках и CD8+ Tc1 (цитотоксических) Т-клетках, и позже на Th17 Т-клетках, регуляторных Т клетках и клетках врожденного иммунитета. TIM-3 активируются, главным образом, его широко экспрессируемым лигандом, галектином-9, ведя к гибели эффекторных Т-клеткок путем поступления кальция в клетку, клеточной агрегации и апоптоза. Когда TIM-3 сигналинг активен, интерферон-продуцирующие Т-клетки становятся истощенными, ведя к супрессии Th1 и иммунной толерантности. Tim-3 экспрессия традиционно наблюдается во время хронической инфекции как характерный маркер истощенных Т клеток.

В канцере опухоль-инфильтрирующие лимфоциты, экспрессирующие TIM-3, описаны в меланоме, неходжкинской лимфоме, раке легкого, желудка и других карциномах. В этих изучениях Tim-3 cо-экспрессируется с PD-1 и ассоциируется с истощением и дисфункцией эффекторных Т-клеток. Этот феномен также наблюдается в мышиных моделях солидных карцином и гемобластозов, где Tim3+ PD1+ CD8+ Т-клетки показывают истощенный фенотип, характеризуемый редуцированной пролиферацией и дефектной продукцией IL-2, TNFα и IFN-γ. Напротив, TIM-3 позитивные Treg показывают повышенную экспрессию эффекторных молекул и более иммуносупрессорны, чем их TIM-3 негативные копии.

Ингибирование только одного TIM-3 слабо влияет на рост опухоли в доклинических мышиных моделях, несмотря на некоторое свидетельство, поддерживающее реверсирование истощения иммунных клеток. Однако, комбинированный таргетинг PD-1 и TIM-3 ведет к выраженному замедлению роста опухоли, больше, чем любой из этих путей в многочисленных, доклинических in vivo моделях, поддерживая концепцию, что злокачественные клетки становятся резистентными к блокаде PD-1 чекпоинта, активируя другой иммунный чекпоинт. Действительно, мышиные модели, частично отвечающие на ингибирование PD-L1, повышенно регулируют Tim-3 экспрессию в резистентных опухолях, и добавление блокады TIM-3 успешно преодолевает эту резистентность. Апрегуляция TIM-3 также наблюдалась у пациентов, получавших монотерапию PD-L1, предполагая, что это может представлять форму адаптивной резистентности к этой терапии. Четыре клинических исследования ранней фазы в стадии реализации, которые пытаются комбинировать анти-PD-L1 терапию с агентами, таргетирующими TIM-3 (Таблица 1).

TIGIT

Трансмембранный протеин TIGIT (T cell Immunoglobulin and ITIM domain) является рецептором, который действует как иммунный чекпоинт для T и NK клеток посредством двух иммунорецепторных тирозин-базисных ингибиторных последовательностей (immunoreceptor tyrosine-based inhibitory motifs , ITIM) в его цитоплазматическом хвосте. Существует два основных лиганда TIGIT (CD155 и CD112), преимущественно экспрессируемых на антиген-представляющих клетках, и однин недавно открытый лиганд, названный нектин-2. Иммуносупрессорные действия TIGIT, видимо, имитируют взаимодействия CTLA-4 с клеточно-поверхностным рецептором B7. Связывание CD155 с CD226 (рецептор на T и NK клетках) ведет к активации эффекторных функций, которые ингибируются, когда CD155 вместо этого связывается с TIGIT.

Мыши с дефицитом TIGIT сенситивны к аутоиммунному артриту. В канцере блокада TIGIT ведет к регрессии опухоли, повышенной выживаемости и устойчивости к опухолевому вызову в мышиных моделях меланомы и рака толстого кишечника. О высокой экспрессии TIGIT mRNA и высоких уровней TIGIT+ лимфоцитов проточной цитометрией сообщили в человеческой почечно-клеточной карциноме, меланоме, раке легкого, молочной железы и пищевода.

В меланоме NY-ESO-1-специфические TIGIT+ CD8+ Т клетки cо-экспрессируют другие маркеры иммунных чекпоинтов, такие как PD-1 и TIM-3. Блокада TIGIT и PD-1 in vitro повышает продукцию IFN-γ и TNF-α опухоль-специфическими CD8+ Т клетками. Популяция ранних эффекторных TIL, которые экспрессируют TIGIT и другие ингибиторные рецепторы (LAG-3, TIM-3 и PD-1), но сохраняют их функциональный фенотип, описана у пациентов с раком легкого. Экспрессия TIGIT гена на средблюдается в базальноподобном раке молочной железы, где, подобно другим биомаркерам иммунного распознавания, она ассоциирована с улучшенной выживаемостью в случае этой агрессивной болезни. Ингибиторы TIGIT находятся все еще в ранних фазах исследований, но, по меньшей мере, два агента (MTIG7192A, OMP-313M32) тестируются в клинических изучениях (Таблица 1).

B7-H3

B7-H3 (CD276) является членом B7 суперсемейства иммуномодулирующих лигандов, тесно связанных с B7-H1 (PD-L1), B7-DС (PD-L2), B7-H2 (ICOS-L) и CTLA-4 лигандами B7-1/B7-2 (CD80/CD86).

Роль B7-H3 в иммунной регуляции спорна, поскольку ранние изучения описали его как иммунный костимулятор, но последующие изучения показали коингибиторную роль.

B7-H3 высоко экспрессируется в нормальных тканях, а также в меланоме и различных карциномах; в большинстве случаев экспрессия ассоциирована с более плохими исходами.

Эноблитузумаб (MGA271), моноклональное антитело, таргетирующее B7-H3, ингибирует опухолевый рост в ксенотрансплантатах карцином почки и мочевого пузыря и в настоящее время исследуется по меньшей мере в четырех клинических исследованиях 1 фазы, включая комбинации с пембролизумабом или ипилимумабом. Предварительные результаты единичного агента (NCT01391143) сообщают о хорошей переносимости и уменьшении объема опухолей (2-69% за 12 недель) для несколько типов опухолей. Моноклональное антитело против B7-H3, маркированное иодом 131 для внутриопухолевой доставки и лучевой терапии, показало перспективу в доклинических изучениях и исследуется в клинических исследованиях 1 фазы. MGD009, ретаргетирующий протеин с двойным аффинитетом, биспецифический для B7-H3 и CD3, изучается на сходной стадии (Таблица 1).

Таблица 1. Обзор последних и современных клинических исследований использования ингибиторов иммунных чекпоинтов в канцере.

VISTA

Vdomain containing Ig Suppressor of T cell Activation (VISTA, другие названия PD-1H, DD1a; имя гена DIES1), недавно открытый иммуно-регуляторный протеин со структурой, подобной B7 Ig суперсемейству, которое включает PD-L1, экспрессируемый в лимфоидных органах и на миелоидных клетках. Функции VISTA как иммуносупрессорного рецептора и лиганда на Т-клетках, понижаемая IFN-γ и TNFα, блокирует пролиферацию Т клеток и повышает конверсию наивных Т-клеток в регуляторные Т клетки.

В мышиных моделях, блокада VISTA повышает иммунную инфильтрацию опухолей, предпочтительно уменьшая супрессорные клетки миелоидного происхождения. Комбинирование анти-VISTA и анти-PDL1 агентов уменьшает объем опухоли и повышает выживаемость. У людей VISTA+ TIL наблюдаются у 46% пациентов с раком желудка с небольшим процентом опухолевых клеток, также экспрессирующих VISTA. Oliveira P с соавт. показал, что эпигенетические факторы могут регулировать экспрессию VISTA в раковых клетках желудка и что VISTA ассоциирован с фенотипом эпителиально-мезенхимального транзита. У пациентов с плоскоклеточной карциномой полости рта экспрессия VISTA ассоциирована с плохой полной выживаемостью в случае низкого количества CD8+ TIL [102]. VISTA+ TIL и макрофаги повышенно регулируются у пациентов с раком простаты и с меланомой после терапии ипилимумабом (анти-CTLA-4) с большим процентом VISTA+ макрофагов с иммуносупрессорным M2 фенотипом, предполагая, что VISTA может представлять компенсаторный механизм резистентности. Начаты клинические исследования 1 фазы анти-VISTA агентов (Таблица 1) с комбинаторными стратегиями, ожидаемыми после установления безопасности агентов.

Костимуляторные рецепторы лимфоцитов

ICOS и ICOS-L

Inducible T-cell Costimulator (ICOS, CD278, H4, AILIM) is a receptor in the CD28 family of B7-binding proteins [104–106], expressed primarily by activated T cells [107–110]. Upon binding of ligand ICOSL (B7-H2, B7 h, GL50, B7RP-1, LICOS, KIAA0653) expressed mainly on antigen presenting cells [111–118] ICOS enhances Th1 and Th2 function largely through augmented production of effector cytokines (IL-4, IL-5, IL-10, IL-21, IFNγ, TNFα) [104,108,110,119,120].

Expression of ICOS and ICOS-L has been observed in human cancers, with variable prognostic implications [121–128]. Mice and human clinical trial patients treated with anti-CTLA-4 or anti-PD-1 agents exhibit an increased treatment response in the presence of ICOS-hi T cells [129–135], suggesting the latter may be a marker of clinical benefit [131,136]. ICOS knockout mice do not respond well to anti-CTLA-4 therapy [137], whereas concomitant CTLA-4 blockade and ICOS stimulation has a superior anti-tumor effect [129]. Together, these results suggest that the ICOS pathway is critical for effective response to CTLA4 (and perhaps other immune checkpoint) inhibition. Similar to TIM-3, it is unlikely that ICOS-agonists will be pursued as a monotherapy, as they do not independently induce a cytotoxic immune response [138]. Based on encouraging results in preclinical animal models [139], an ICOS agonist antibody JTX-2011 is being investigated in the phase 1 ICONIC clinical trial in combination with nivolumab (NCT02904226), and has so far been well-tolerated [140]; ICOS agonist GSK3359609 is also being evaluated in phase I trials (INDUCE-1, NCT02723955) in combination with pembrolizumab (Table 1).

CD27 и CD70

Members of the tumor necrosis factor (TNF) receptor superfamily contribute to immune upregulation by a mechanism of action different from B7/CD28 co-stimulatory interactions. One well-known member, CD27, is expressed exclusively on lymphocytes [141–144]. Even naпve CD4+ and CD8+ T-cells express low levels CD27; upon activation, CD27 is strongly upregulated on cell surfaces [145] and shed in a soluble form [146,147]. CD27 signalling is limited by the degree of expression of its ligand CD70, which is restricted to T cells, B cells, and dendritic cells following activation of an antigen receptor [148–151]. CD27/CD70 signalling boosts T-cell clonal expansion and survival [152–158], promotes effector and memory T-cell differentiation [152,154,157,159–166], and enhances activation and function of B and NK  cells  [151,167–172].

In a transgenic mouse model, forced expression of CD70 constitutively activates the CD27/CD70 axis, upregulating effector T cells [173] and protecting against tumor development [174]. CD27 agonist therapy also prevents tumor formation or progression in immunocompetent preclinical mouse models [171,175–179]. Varlilumab, a CD27 agonist, is being investigated in multiple early phase clinical trials alone and in combination with anti-PD-1 (Table 1). Preliminary results report that varlilumab treatment upregulates chemokine production, T-cell stimulation, and Treg depletion; 8/31 melanoma/renal cell carcinoma patients had stable disease (SD) at 3 months [180], and of 15 lymphoma patients in a different study, there was 1 partial response (77% reduction) and 3 SD [181]. The related strategy of targeting CD70 is the subject of three antibody-drug conjugates and one monoclonal antibody undergoing clinical trials (Table 1). MDX-1203 (NCT00944905) was well-tolerated and achieved SD in 16/23 (69%) of patients. [182]. SGN-75, an antibody-drug conjugate linking an antiCD70 antibody with cytotoxic agent monomethyl auristatin F (NCT01015911), was also well-tolerated and elicited responses in renal cell carcinomas and lymphomas; however, development was discontinued in favour of a new antibody drug conjugate, SGNeCD70A, in which an anti-CD70 antibody is conjugated to pyrrolobenzodiazepine (NCT02216890).

GITR

Glucocorticoid-Induced TNF Receptor (GITR) — трансмембранный рецептор II типа , член суперсемейства TNFR, конститутивно экспрессируемый на регуляторных Т клетках и индуцируемый на активных CD8+ и CD4+ Т клетках. GITR связывание с GITR-L (экспрессируемый на антиген-представляющих клетках), ингибирует активность Treg и стимулирует эффекторные Т-клетки, делая активацию GITR привлекательной стратегией противоопухолевой иммунотерапии.

Много доклинических сообщений о GITR противоопухолевой in vivo активности использовали мышиное GITR агонистическое моноклональное антитело IgG1 (DTA-1) в мышиных моделях солидного рака. GITR агонизм в дополнение к истощению и ингибированию Treg (подобно CTLA-4 антагонистам и OX40 агонистам), супрессирует продукцию IL-10 и супрессорные клетки миелоидного ростка. Комбинирование GITR агонистов с другими иммуномодулирующими агентами ведет к аддитивным противоопухолевым эффектам.  Одна из наиболее интересных находок этих изучений — то, что GITR агонисты супрессируют рост опухоли и повышают выживаемость не только в моделях иммуногенных опухолей (толстый кишечник, мочевой пузырь, легкое, меланома), но также и в слабо иммуногенных опухолях (молочной железы, мышиной модели меланомы B16, яичника), помещая GITR агонистов в уникальную позицию по сравнению с другими ингибиторами иммунных чекпоинтов, для которых предуществующий иммунитет, видимо, является предпосылкой для их эффективности. Иммуногистохимически или проточной цитометрией, об экспрессии GITR сообщили во многих солидных опухолях человека. У больных с раком молочной железе и эндометрия, GITR экспрессия на Treg выше в TIL, чем в периферической крови. Прогностическое значение GITR+ TIL еще не изучено полностью. По меньшей мере четыре GITR агониста исследуются одни и в комбинациях с другими ингибиторами чекпоинтов в клинических исследованиях ранней фазы (Таблица 1).

Врожденный иммунитет

Макрофагальные чекпоинты

CD47 и SIRPα

CD47, первоначально идентифицированный как Integrin-Associated Protein (IAP), является иммуноглобулином клеточной поверхности, который негативно регулирует противоопухолевый иммунитет посредством супрессии фагоцитоза. Экспрессируемый повсеместно в нормальных тканях, CD47 функционирует, в частности, для защиты жизнеспособные эритроциты от фагоцитоза. Сигналинг вызывается взаимодействием с его лигандом SIRPα (сигнал-регуляторный протеин α), иммуноглобулином клеточной поверхности, преимущественно экспрессируемым макрофагами и дендритными клетками.

Activation of SIRPα by CD47 suppresses phagocytosis by preventing myosin-II accumulation at the phagocytic synapse and suppressing the respiratory burst. T-cell activation is secondarily decreased as an indirect result of reduced tumor cell ingestion by antigen-presenting cells; furthermore, activation of CD47 on naпve T-cells promotes the formation of Tregs and inhibits formation of T helper 1 effector cells.

Overexpression of CD47 has been observed across most cancers [218–225], suggesting that malignant cells exploit the CD47/SIRPα “don’t eat me” signal to evade phagocytosis. In translational studies, high CD47 mRNA expression levels correlate with poor clinical outcomes. [223,225–233] In vitro, CD47/SIRPα blockade induces phagocytosis of cancer cells by human and mouse macrophages [221–223,225,226]. Anti-CD47 monoclonal antibodies have impressive activity in xenograft models [221–226,234,235], although because human CD47 binds exceptionally well to the SIRPα of the NOD-scidIL2Rgammanull mice used [236,237], some studies may overestimate the degree of efficacy [238].

Many early phase clinical trials are in progress targeting the CD47/ SIRPα axis (Table 1). Toxicity data has been presented for NCT02216409, a trial investigating anti-CD47 antibody Hu5F9-G4, [235] which was well-tolerated in 16 patients with advanced solid tumors.

IDO

Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which in the immune compartment is found in macrophages and dendritic cells, where it catalyzes the first, rate-limiting step of tryptophan catabolism. In converting tryptophan to kynurenine, IDO impacts immune surveillance in two ways: 1) depletion of tryptophan impairs T-cell proliferation due to amino acid insufficiency, and 2) kynurenine induces apoptosis of Th1 cells and promotes differentiation of naive T cells to regulatory T cells. This generates an immune-privileged environment, as seen in the placenta, where IDO was first isolated.

Numerous cancer types have been shown to constitutively express IDO. Transfecting cell lines with IDO prevents their rejection in tumor antigen-immunized mice, an effect reversible with IDO inhibitors. Pharmacological inhibition of IDO has been shown in numerous mouse tumor models to stimulate a robust T cell response and inhibit tumor progression. The tumor suppressor BIN1, which controls expression of IDO, is deficient in numerous cancers; BIN1 knockout induces higher levels of IFNγ-stimulated IDO expression and results  in larger tumors in immunocompetent mouse models compared to controls.

There are presently four small molecule inhibitors of IDO under investigation in clinical trials. One of these, epacadostat, is registered to 20 clinical trials, including one phase 3 trial, and in patients with advanced malignancies, stable disease =16 weeks was observed in 7/52 patients (no objective response). In combination with anti-PD-1 agent pembrolizumab, reductions in tumor burden were observed in 15/19 patients with advanced solid malignancies, including 2 complete responses in melanoma patients.

Чекпоинты естественных киллерных клеток

KIR семейство

KIR (Killer Immunoglobulin-like Receptor) семейство состоит из высоко полиморфных генов, экспрессируемых на клеточной мембране большинства NK и некоторых Т клеток. Некоторые члены KIR семейства (KIR2DL1-3, KIR3DL1) ассоциируются с ингибиторными функциями путем связывания с MHC молекулами (HLA-C/HLA-B). Экспрессия KIR на NK клетках представляет один из механизмов обучения NK клеток от самораспознавания. Сильные взаимодействия между ингибиторными KIR рецепторами и HLA лигандами могут преодолевать NK активирующие сигналы.

Вследствие своей высоко полиморфной природы, различные KIR гены и лиганды влияют на риск заболевания, включая аутоиммунитет и рак. Комбинации KIR генов KIR и специфических лигандов ассоциированы с риском рака. Активирующие KIR гены (KIR2DS2, KIR2DS3 и KIR2DS4) ассоциированы с улучшенной выживаемостью пациентов с колоректальным раком и глиобластомой. Активирующие KIR гены (KIR2DS2, KIR2DS3 и KIR2DS4) ассоциированы с улучшенной выживаемостью в колоректальном раке и пациентах с глиобластомой. В мышиных моделях сконструированные химерные антигенные рецепторы, экспрессирующие NK-активирующий KIR2DS2, показывают более высокую эффективность, чем традиционные костимуляторные молекулы.

Несмотря на обещающие доклинические результаты, единичный клинически исследуемый агент для миеломной болезни фазы 1/2 IPH2101, антительный ингибитор KIR2DL1, 2, и 3 (IPH2101), не показывал ответов болезни. Последующее коррелативное изучение показывало, что мононуклеары периферической крови пациентов, которые лечили in vitro с IPH2101, вели к удалению KIR2DL1 на NK клетках трогоцитозом из FcγRI-экспрессирующих антиген-представляющих клеток. Соответственно, наблюдалось уменьшение цитотоксической активности NK клеток, которое могло объяснить неспособность активировать NK клетки у пациентов в клиническом исследовании. Другой KIR2DL1/2/3 ингибитор (IPH2102, лирилумаб) в настоящее время находится в клинических исследованиях фазы 1/2 в распространенных солидных раках и гемобластозах в комбинации с PD-1 или CTLA-4 блокадой (Таблица 1). Предварительные результаты сообщают, что обнадеживающая объективная величина ответа 24% у пациентов с распространенным раком головы и шеи, леченных лирилумабом в комбинации с анти-PD1 (ниволумабом).

CD94/NKG2A

CD94 — рецептор инвариантной цепи, который на NK клетках может формировать ингибиторный гетеродимер с членом лектин C типа-подобного семейства NKG2A или активирующий гетеродимер с NKG2C или E. Т клетки также могут экспрессировать CD94/NKG2A рецептор (хотя к меньшей степени по сравнению с NK клетками), где он функционирует как преобладающий ингибиторный чекпоинт. Связывание с MHC I класса (HLA-E) опосредует ингибиторную функцию CD94/NKG2A после лигации TCR. CD94/NKG2A-HLA-E взаимодействие может блокироваться таргетингом ERAP-1, протеин, необходимого для обеспечения функциональныи лигандами для CD94/NKG2A на HLA-E молекулах.

CD94/NKG2A как активную мишень для противоопухолевой иммунотерапии. Действительно, множественные изучения сообщают о присутствии CD94/NKG2A+ клеток у онкологических больных. Образцы крови от молодых пациентов с колоректальным раком показывают повышенное число NKG2A+ NK клеток с более низкой цитотоксической активностью по сравнению с образцами от здорового контроля.

Экспрессия NKG2A на NK клетках выше в опухолях против периферической крови пациентов с раком легкого и раком шейки матки.

В небольшой когорте пациентов с раком полости рта сообщили о более высокой частоте NKG2A+ NK, инфильтрирующих опухоль по сравнению с нормальной слизистой оболочкой. Самая высокая экспрессия NKG2A+ NK клеток наблюдались в гнездах рака с низким количеством CD8+ TIL, которые были негативны для Ki67. В гепатоцеллюлярной карциноме большое число NKG2A+ NK клеток найдены во внутриопухолевом по сравнению с перитуморальными регионами. Эти находки поддерживают релевантность NKG2A ингибиторных механизмов как важный путь иммунной эвазии в опухолях человека. Пр по ходят меньшей мере шесть клинических исследований 1/2 фаз изучают IPH2201 антитело, таргетирующее NKG2A у больных с различными карциномами поздних стадий, некоторые в комбинации с PD-L1 ингибиторами (Таблица 1).

Дискуссия

The success of early immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 has led to a surge in research and development of resources devoted to cancer immunotherapy. How these emerging targets and drugs will be incorporated into the clinical practice is one of the major focuses of clinical cancer research today. There is evidence for additive anti-tumor activity but also higher adverse effects of strategies combining CTLA-4 and PD-1 checkpoint inhibitors [1,2]. Many agents listed in this review are being evaluated in combination with PD1 and/or CTLA-4 inhibitors (Table 1), with unresolved issues including not only efficacy and toxicity, but also optimal sequential delivery in patients and identification of predictive biomarkers of response.

At present, few predictive biomarkers of response to immune checkpoint inhibitors are in use. The best tests to support PD-1/PD-L1 agents are a subject of great controversy, and most new agents do not have validated companion biomarkers. However, inflamed tumors are associated with an elevated response to immune checkpoint inhibitors, and frequently comprise tumors with a high mutational load or with microsatellite instability[13,298], the latter now considered an FDA-approved biomarker for pembrolizumab independent of tumor site or histology. Immune response profiling by next generation  panel sequencing or technologies such as NanoString may also prove useful in this regard and are a subject of active research in clinical trial correlative science studies. In contrast, immune-desert (socalled “cold”) tumors have only modest responses to immune checkpoint inhibitors and may need to  be treated  using  immunostimulatory approaches [299]. Clinical trial designs that include assessment of immune biomarkers (e.g., T cell receptor sequencing), access to early on-treatment biopsies for immune monitoring, and identification of peripheral blood biomarkers that correlate with the tumor immune microenvironment may help to address these issues.

Заключение

This field is rapidly advancing and extremely active for drug development and clinical trials. Toxicities still need to be determined, particularly of combination strategies, which risk enhanced autoimmune side effects. Given limited resources and patients available for clinical trials, emerging agents with acceptable toxicity will need to be prioritized based on factors including not only the strength of evidence implicating their role in cancer immuno-oncology, but also their frequency of expression in areas of clinical need not well-served by existing agents. While many of these agents may not ultimately find a place in the growing armamentarium of anticancer immuno-oncology drugs, the pathways under investigation are so many, and the early data so promising, that it is likely that several truly effective new treatment strategies will emerge.

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