safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2020-8-1-9-22safetyrisk-168Research ArticleОБЗОРЫREVIEWSИнгибиторы контрольных точек иммунного ответа: новые риски нового класса противоопухолевых средствImmune Response Checkpoint Inhibitors: New Risks of a New Class of Antitumor Agentshttps://orcid.org/0000-0002-2888-5993ШубниковаЕ. В.ShubnikovaE. V.

Шубникова Елена Владимировна, канд. мед. наук

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Elena V. Shubnikova, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

shubnikovaev@expmed.ruhttps://orcid.org/0000-0002-7597-2926БукатинаТ. М.BukatinaT. M.

Букатина Татьяна Михайловна, канд. мед. наук

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Tatyana M. Bukatina, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

Bukatina@expmed.ruhttps://orcid.org/0000-0002-9514-6322ВельцН. Ю.VeltsN. Yu.

Вельц Наталья Юрьевна, канд. биол. наук, доцент

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Nataliya Yu. Velts, Cand. Sci. (Biol.), Associate Professor

8/2 Petrovsky Blvd, Moscow 127051

Velts@expmed.ruhttps://orcid.org/0000-0003-4478-1219КаперкоД. А.KaperkoD. A.

Каперко Дмитрий Алексеевич

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Dmitry A. Kaperko

8/2 Petrovsky Blvd, Moscow 127051

Kaperko@expmed.ruhttps://orcid.org/0000-0002-0522-0307КутеховаГ. В.KutekhovaG. V.

Кутехова Галина Викторовна

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Galina V. Kutekhova

8/2 Petrovsky Blvd, Moscow 127051

Kutekhova@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation20202701202081922Copyright © Шубникова Е.В., Букатина Т.М., Вельц Н.Ю., Каперко Д.А., Кутехова Г.В., 20202020Шубникова Е.В., Букатина Т.М., Вельц Н.Ю., Каперко Д.А., Кутехова Г.В.Shubnikova E.V., Bukatina T.M., Velts N.Y., Kaperko D.A., Kutekhova G.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/168

Введение в клиническую практику ингибиторов иммунных контрольных точек, блокирующих цитотоксический Т-лимфоцит-ассоциированный протеин 4 (CTLA-4), белок запрограммированной клеточной гибели-1 (PD-1) и лиганд рецептора запрограммированной клеточной гибели (PD-L1), позволило улучшить прогноз пациентов со злокачественными новообразованиями различной локализации. Противоопухолевое действие ингибиторов иммунных контрольных точек основано на блокаде сигнальных путей CTLA-4 и PD-1/PD-L1 и усилении противоопухолевой активности лимфоцитов. Однако ингибирование иммунных контрольных точек может приводить к нарушению регуляции иммунных ответов и возникновению нового вида нежелательных реакций, связанных с изменением активности иммунокомпетентных клеток в организме. Цель работы: анализ нежелательных реакций, связанных с применением ингибиторов иммунных контрольных точек. Показано, что структура иммуноопосредованных нежелательных реакций различалась в зависимости от класса ингибиторов иммунных контрольных точек. Частота развития иммуноопосредованных нежелательных реакций была выше при использовании ингибиторов CTLA-4, чем ингибиторов PD-1/PD-L1, и значительно возрастала на фоне комбинированной терапии. При терапии ингибиторами CTLA-4 чаще наблюдались реакции со стороны кожи (сыпь, кожный зуд), желудочно-кишечного тракта (диарея, колит), эндокринных желез (гипофизит). При лечении ингибиторами PD-1 преобладали нарушения со стороны органов дыхания (пневмонит), реже отмечались нарушения со стороны желудочно-кишечного тракта (диарея, колит), кожи (сыпь, зуд) и эндокринных желез (гипотиреоз). Терапия ингибиторами PD-L1 сопровождалась развитием пневмонита. При развитии иммуноопосредованных нежелательных реакций может потребоваться прекращение лечения и введение иммунодепрессантов, в связи с этим ранняя диагностика и своевременная терапия осложнений служат важными критериями успешного проведения противоопухолевой терапии. Дальнейшее изучение механизмов развития иммуноопосредованных нежелательных реакций позволит оптимизировать противоопухолевую терапию ингибиторами иммунных контрольных точек.

The introduction into clinical practice of immune checkpoint inhibitors that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1), has improved the prognosis of patients with malignant neoplasms of diff erent localisation. The antitumour eff ect of immune checkpoint inhibitors is based on blocking CTLA-4 and PD-1/PD-L1 signaling pathways and enhancing lymphocyte antitumour activity. However, inhibition of immune checkpoints may lead to dysregulation of immune responses and appearance of a new type of adverse reactions resulting from changes in the activity of immunocompetent cells. The aim of the study was to analyse adverse reactions associated with the use of immune checkpoint inhibitors. It was demonstrated that the structure of immune-mediated adverse reactions varied depending on the class of immune checkpoint inhibitors. The incidence of immune-mediated adverse reactions was higher with CTLA-4 inhibitors as compared with PD-1/PD-L1 inhibitors, and increased signifi cantly in the case of combination therapy. The treatment with CTLA-4 inhibitors most often resulted in skin reactions (rash, itching), gastrointestinal tract reactions (diarrhea, colitis), and endocrine gland problems (hypophysitis). The treatment with PD-1 inhibitors most often led to respiratory disorders (pneumonitis), and in some cases to gastrointestinal disorders (diarrhea, colitis), skin reactions (rash, itching), and endocrine gland problems (hypothyroidism), but they were less common. The treatment with PD-L1 inhibitors was associated with the development of pneumonitis. The development of immune-mediated adverse reactions may require discontinuation of treatment and administration of immunosuppressants, therefore early diagnosis and timely treatment of complications are important prerequisites for successful antitumour therapy. Further study of the mechanisms of immune-mediated adverse reaction development will optimise antitumour therapy with immune checkpoint inhibitors. 

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The authors declare that there are no conflicts of interest present.