Cancer Immunotherapy Based on the Blockade of Immune Checkpoints

Боголюбова, А. В.; Efimov, Grigory A.; Друцкая, М. С.; Недоспасов, С А

doi:10.15789/1563-0625-2015-5-395-406

Cited by 8 publications

(4 citation statements)

References 73 publications

(88 reference statements)

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“…В норме обеспечивается баланс между ингибирующими и стимулирующими сигналами [12], однако при различных нарушениях в системе иммунитета развиваются, например, патологическая ИТ, приводящая к появлению злокачественных опухолей, или аутоагрессия, приводящая к аутоиммунным заболеваниям. При злокачественных новообразованиях вышеперечисленные молекулы (CTLA-4, PD-1 и PD-L1) осуществляют негативную регуляцию процессов активации, дифференцировки и эффекторной функции Т-лимфоцитов, необходимых для реализации противоопухолевого клеточного иммунитета [13,14]. Моноклональные антитела к ингибиторам контрольных точек (check point inhibitors) иммунного ответа устраняют "блок" иммунной системы, не позволяющий ей воздействовать на опухолевые клетки.…”

Section: механизм действия моноклональных антителингибиторов контрольunclassified

“…Вышеперечисленные лекарственные средства изменили прогноз ряда онкологических заболеваний, таких как распространенные формы меланомы и немелкоклеточный рак легкого. Вместе с тем применение моноклональных антител может стать триггером развития аутоиммунных и воспалительных заболеваний эндокринных органов, желудочно-кишеч-ного тракта, печени, кожи [6,14]. В настоящее время нежелательные явления, связанные с вовлечением иммунной системы, выделяют в отдельный класс: IRAEs -immune-related adverse events [11].…”

Section: механизм действия моноклональных антителингибиторов контрольunclassified

“…Суммируя вышесказанное, необходимо отметить, что появление высокоэффективных препаратов для лечения прогрессирующих онкологических заболеваний обеспечило увеличение продолжительности безрецидивной жизни [14] при многих еще недавно фатальных формах рака, но одновременно поставило новые задачи перед онкологами и эндокринологами -своевременное выявление аутоиммунных эндокринопатий как осложнений терапии основной патологии. Необходимо отметить, что развивающиеся на фоне лечения ингибиторами контрольных точек эндокринные заболевания могут манифестировать тяжелыми жизнеугрожающими состояниями -микседематозной комой, аддисоническим кризом, кетоацидотической комой, в связи с чем требуется регулярный контроль функции органов-мишеней [8,33].…”

Section: заключениеunclassified

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Lesions in endocrine glands as a complication of immunotherapy in the practice of oncologist

et al. 2019

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This review describes the lesions of the endocrine system that occur as a result of immunotherapy of cancer. This phenomenon is associated with the inhibition by monoclonal antibodies of checkpoints, which do not allow the immune system to affect tumor cells: CTLA-4, PD-1 and PD-L1. Immunotherapy by this group of drugs allows to increase the life expectancy of patients with cancer, but it also leads to the development of autoimmune endocrinopathies (thyroiditis, adrenalitis, diabetes mellitus, hypophysitis), which often manifest by life-threatening conditions. In view of the above, the necessity to carry out regular monitoring of the function of target organs in patients receiving immunotherapy for malignant tumors is discussed. On the other hand, the phenomenon of developing the autoimmune endocrinopathies during therapy with immunological checkpoints inhibitors is of fundamental interest to endocrinologists. Iatrogenic lesions of the endocrine system are unique models of initiation of immune autoagression. Thus, the development of adrenalitis in patients receiving treatment with a PD-1 inhibitor suggests that the PD-1 is involved in the pathogenesis of autoimmune adrenal insufficiency in patients not receiving treatment with this drug. Thus, clarification of the role of PD-1 in the development of adrenalitis is required. The results of such investigations will allow to identify the risk groups for the development of autoimmune adrenal insufficiency and, accordingly, timely diagnosing it and beginning treatment.

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Section: механизм действия моноклональных антителингибиторов контрольunclassified

Section: заключениеunclassified

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Lesions in endocrine glands as a complication of immunotherapy in the practice of oncologist

et al. 2019

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“…Немаловажная роль в противоопухолевом им мунном ответе отводится Тлимфоцитам, в частности регулированию экспрессии молекул, участвующих в формировании иммунологического синапса [13]. В основе патогенеза заболевания лежат нарушение апоптоза опухолевых клеток, а также их способность вызывать анергию Тлимфоцитов и тем самым избегать иммунного надзора.…”

Section: Introductionunclassified

Expression features of antigens involved in the formation of immunological synapse in splenic marginal zone lymphoma

et al. 2020

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Background. Splenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin’s B-cell lymphoma. It presents morphologically by mature lymphoid B-cells. They conform to these immunological characteristics of marginal zone lymphocytes from secondary follicles. The tumor B-cells of SMZL do not have specific markers of immunophenotype and requires the exclusion of other non-Hodgkin’s B-cell lymphomas. There is an annual increase in the incidence of SMZL. There are refractory forms and progressive course of the SMZL. There is a huge variety of the mechanisms of evading tumor cells from immunological control. Unlike solid tumors, B-lymphoproliferative diseases are characterized by the expression of HLA I/II and co-stimulatory molecules (CD80 and CD86). Therefore, tumor B-lymphocytes can act as antigen-presenting cells (APC) for T lymphocytes. The T-cell immune response is known to play an important role in antitumor control. It is known that effective activation of T-lymphocytes requires the formation of an immunological synapse and the presence of two activation signals (antigen recognition and co-stimulation of CD28-CD80/86). According to the modern concept of tumor development, there is a gradual selection of tumor clones. As a result, only tumor cells that are invisible to the immune system remain. Mechanisms of evasion of tumor B-cells of SMZL from immune surveillance are currently not fully understood and are being actively studied.Objective: to study the expression features of antigens involved in the formation of immunological synapse in patients with SMZL in peripheral blood.Materials and methods. The study includes 10 primary SMZL patients; all patients have stage IV according to the Ann Arbor classification. Splenectomy was performed for all patients as a first stage of treatment. Two patients had progression of SMZL after splenectomy, which required chemotherapy. The control group included 25 healthy donors. Peripheral blood was used as a material for analysis. The study was conducted on a 6-color BD FACS Canto II flow cytometer (BD Biosciences, USA) immediately after diagnosis.Results. Tumor B-cells of SMZL are different from B-cells of healthy donors with a greater proportion of CD80+, FAS+, PD-1+-cells, which may correspond to activated B-cells. The proportion of CD4+PD-1+ and CD8+PD-1+ T-cells in patients with SMZL was higher in comparison with the control group. There was a large proportion of T-cells expressing PD-1 in the group of patients with SMZL progression after splenectomy in comparison with the group of patients with indolent course of SMZL. Conclusion. Thereby, tumor B-cells of the SMZL retains the features of non-tumor analogues. The most significant mechanism for evading immune surveillance in an SMZL is inhibition of the T-cell immunity via the PD-1–PD-L1 pathway. The most pronounced inhibition of T-cell immunity causes an uncontrolled tumor process.

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