medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2021-20-84-93medsovet-6584Research ArticleОПУХОЛИ ПЕЧЕНИLIVER TUMORSЭффективность ингибитора иммунных контрольных точек ниволумаба в лечении распространенной гепатоцеллюлярной карциномы при исчерпанных возможностях терапии ингибиторами тирозинкиназEfficacy of the immune checkpoint inhibitor nivolumab in the treatment of advanced hepatocellular carcinoma with the exhausted possibilities of therapy with tyrosine kinase inhibitorshttps://orcid.org/0000-0001-7127-7945ГоряиноваА. Ю.GoryainovaA. Yu.

заведующая координационным отделом лекарственного обеспечения, 350040, Краснодар, ул. Димитрова, д. 146;

ассистент кафедры онкологии с курсом торакальной хирургии, 350063, Краснодар, ул. Митрофана Седина, д. 4

Medical Oncologist, Head of the Drug Supply Coordination Department, 146, Dimitrov St., Krasnodar, 350040;

Assistant of the Department of Oncology with the course of Thoracic Surgery, 4, Mitrofan Sedin St., Krasnodar, 350063

mashelueva@yandex.ruhttps://orcid.org/0000-0002-0698-7710СтуканьА. И.StukanA. I.

к.м.н., врач-онколог координационного отдела лекарственного обеспечения, 350040, Краснодар, ул. Димитрова, д. 146;

ассистент кафедры онкологии с курсом торакальной хирургии, 350063, Краснодар, ул. Митрофана Седина, д. 4

Cand. Sci. (Med.), Medical Oncologist, Drug Supply Coordination Department, 146, Dimitrov St., Krasnodar, 350040;

Assistant of the Department of Oncology with the course of Thoracic Surgery, 4, Mitrofan Sedin St.,  Krasnodar, 350063

Jolie86@Bk.Ruhttps://orcid.org/0000-0001-8084-8770МурашкоР. А.MurashkoR. A.

к.м.н., главный врач, 350040, Краснодар, ул. Димитрова, д. 146;

доцент кафедры онкологии с курсом торакальной хирургии, 350063, Краснодар, ул. Митрофана Седина, д. 4

Cand. Sci. (Med.), Head, 146, Dimitrov St., Krasnodar, 350040;

Associate Professor of the Department of Oncology with a Course of Thoracic Surgery, 146, Dimitrov St., Krasnodar, 350040

kkod@kkod.ruhttps://orcid.org/0000-0002-8715-2992ШаровС. В.SharovS. V.

к.м.н., заместитель главного врача по лекарственному обеспечению, 350040, Краснодар, ул. Димитрова, д. 146;

ассистент кафедры онкологии с курсом торакальной хирургии, 350063, Краснодар, ул. Митрофана Седина, д. 4

Cand. Sci. (Med.), Deputy Head for Drug Supply, 146, Dimitrov St., Krasnodar, 350040;

Russia Assistant of the Department of Oncology with the course of Thoracic Surgery, 4, Mitrofan Sedin St., Krasnodar, 350063

dr_sch@mail.ruhttps://orcid.org/0000-0003-0078-1567КирсановаО. И.KirsanovaO. I.

врач-радиолог отдела лучевой диагностики, 

350040, Краснодар, ул. Димитрова, д. 146

Radiologist, 

146, Dimitrov St., Krasnodar, 350040

igorevna-best@mail.ruhttps://orcid.org/0000-0002-6866-1425ЛымарьЕ. В.LymarE. V.

врач-онколог координационного отдела лекарственного обеспечения, 

350040, Краснодар, ул. Димитрова, д. 146

Medical Oncologist, Drug Supply Coordination Department, 

146, Dimitrov St., Krasnodar, 350040

tsari29@mail.ruКлинический онкологический диспансер №1; Кубанский государственный медицинский университетРоссияClinical Oncologic Dispensary No.1; Kuban State Medical UniversityRussian FederationКлинический онкологический диспансер №1; Кубанский государственный медицинский университетРоссияClinical Oncologic Dispensary No.1; Kuban State Medical UniversityRussian FederationКлинический онкологический диспансер №1; Кубанский государственный медицинский университетРоссияClinical Oncologic Dispensary No.1; Kuban State Medical UniversityRussian FederationКлинический онкологический диспансер №1РоссияClinical Oncologic Dispensary No.1Russian Federation2021101220210208493Copyright © Горяинова А.Ю., Стукань А.И., Мурашко Р.А., Шаров С.В., Кирсанова О.И., Лымарь Е.В., 20212021Горяинова А.Ю., Стукань А.И., Мурашко Р.А., Шаров С.В., Кирсанова О.И., Лымарь Е.В.Goryainova A.Y., Stukan A.I., Murashko R.A., Sharov S.V., Kirsanova O.I., Lymar E.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.med-sovet.pro/jour/article/view/6584

Гепатоцеллюлярная карцинома – одно из самых грозных и смертоносных онкологических заболеваний. Ограниченные возможности хирургических методов лечения и формирование множественной лекарственной резистентности, обусловленной биологическими особенностями как самой ткани печени, так и опухолевых клеток с их микроокружением, определяют неудовлетворительные показатели безрецидивной и общей выживаемости пациентов. Кроме того, ставшая «золотым стандартом» терапия ингибиторами тирозинкиназ, имеет ограниченные возможности: большое количество побочных эффектов значительно снижает качество жизни и приверженность к лечению у больных гепатоцеллюлярным раком. Поиск молекулярнобиологических мишеней, а также новых терапевтических агентов, блокирующих эти мишени, не всегда приводит к позитивным результатам. Иммунотерапия в этом смысле является приоритетом, обладая хорошей переносимостью, низким количеством побочных эффектов, отсутствием необходимости дополнительного тестирования биологического материала пациента перед началом лечения, высокой эффективностью и длительностью ответа. Однако существует много нерешенных вопросов о  длительности терапии, прогнозировании ее эффективности, оптимальной комбинации препаратов или использовании монотерапии, формировании приоритетных подгрупп больных. Понимание механизмов уклонения от  иммунного ответа, способностью к которому обладает гепатоцеллюлярная карцинома, – это ключ к успешному использованию иммунотерапевтических агентов в самостоятельном варианте, в сочетании с тирозинкиназными ингибиторами, антиангиогенными препаратами или между собой.

В  настоящей статье представлен обзор данных клинических исследований современных лекарственных препаратов для лечения гепатоцеллюлярной карциномы, описан механизм иммунологической толерантности печени в качестве возможного предиктивного маркера чувствительности к иммунотерапии. Представляется перспективным изучение роли клеток микроокружения гепатоцеллюлярной карциномы для прогнозирования эффективности иммунотерапии. На клиническом примере продемонстрирован успешный опыт использования иммунотерапевтического препарата ниволумаб при резистентности гепатоцеллюлярной карциномы к ингибиторам тирозинкиназ. Классический пример продолжительности ответа на терапию, отсутствие реактивации хронического вирусного гепатита, а также управляемая токсичность – все эти показатели дают возможность клиницисту рассматривать иммунотерапию в качестве приоритетной опции для лечения неоперабельной гепатоцеллюлярной карциномы. 

Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma. 

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