Journal of Modern OncologyJournal of Modern OncologyСовременная онкология1815-14341815-1442LLC Obyedinennaya Redaktsiya11494910.26442/18151434.2023.1.202168CLINICAL ONCOLOGYКЛИНИЧЕСКАЯ ОНКОЛОГИЯResearch ArticleClinical case of complications of immunotherapy – encephalitisКлинический случай осложнения иммунотерапии – энцефалитhttps://orcid.org/0000-0002-9558-55798220-2854LyadovaMarina A.ЛядоваМарина Александровна
Russian Federation

Cand. Sci. (Med.), City Clinical Oncology Hospital №1

канд. мед. наук, зав. химио- терапевтическим отд-нием ГБУЗ «ГКОБ №1»

dr.lyadova@gmail.comhttps://orcid.org/0000-0002-1568-8683KuchevskayaOlesya A.КучевскаяОлеся Александровна
Russian Federation

Oncologist, City Clinical Oncology Hospital №1

врач-онколог отд-ния дневного стационара ГБУЗ «ГКОБ №1»

olesya.kuchevskaya@mail.ruhttps://orcid.org/0000-0002-0319-49342884-4803KulikovaEvgeniya A.КуликоваЕвгения Александровна
Russian Federation

Department Head, City Clinical Oncology Hospital №1

зав. отд-нием лучевой диагностики ГБУЗ «ГКОБ №1»

kulikovaEA14@zdrav.mos.ruCity Clinical Oncology Hospital №1ГБУЗ «Городская клиническая онкологическая больница №1» Департамента здравоохранения г. Москвы1705202325114014428112022Copyright ©; 2023, Consilium MedicumCopyright ©; 2023, ООО "Консилиум Медикум"2023Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://modernonco.orscience.ru/1815-1434/article/view/114949

Nowadays, checkpoint inhibitors are widely used in the treatment of various types of cancer. However, its’ use is often accompanied by the development of immune-mediated adverse events (IAEs) of various systems and organs. Aim – description of the features of the development of encephalitis during the treatment of small cell lung cancer (SCLC) using checkpoint inhibitors. There is a clinical case of a patient, who is receiving immunotherapy, with small cell carcinoma of the upper lobe of the left lung, stage IVA, cT2bN2M1a. The patient sought medical help in connection with complaints of an episode of memory loss, difficulty in remembering new information. Based on the clinical picture and examination data, a limbic encephalitis was diagnosed. Immune-related adverse events might affect any organ during all the period of therapy with checkpoint inhibitors. Physicians shall be aware of the risk of encephalitis development related to this type of anti-cancer therapy.

В настоящее время ингибиторы контрольных точек широко используются в лечении различных видов онкологических заболеваний. Однако их использование часто сопровождается развитием иммуноопосредованных нежелательных явлений со стороны различных органов и систем. Цель – описание особенностей развития энцефалита на фоне лечения мелкоклеточного рака легкого с использованием ингибиторов контрольных точек. Приведен клинический случай пациентки с мелкоклеточным раком верхней доли левого легкого IVA стадии cT2bN2M1а, находящейся на иммунотерапии, которая обратилась за медицинской помощью в связи с жалобами на эпизод потери памяти, сложности при запоминании новой информации. На основании клинической картины и данных обследования установлен диагноз – «лимбический энцефалит». На фоне терапии ингибиторами контрольных точек иммунитета могут поражаться любые органы и системы в течение всего периода лечения. Клиницисты должны быть осведомлены о возможности развития энцефалита после начала данной терапии.

immune checkpoint inhibitorsimmunotherapyatezolizumabsmall cell lung cancerimmune-mediated adverse eventsencephalitisингибиторы контрольных точек иммунитетаиммунотерапияатезолизумабмелкоклеточный рак легкогоиммуноопосредованные нежелательные явленияэнцефалитZhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17(8):807-21. DOI:10.1038/s41423-020-0488-6Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol. 2021;16:223-49. DOI:10.1146/annurev-pathol-042020-042741Chhabra N, Kennedy J. A Review of Cancer Immunotherapy Toxicity: Immune Checkpoint Inhibitors. J Med Toxicol. 2021;17(4):411-24. DOI:10.1007/s13181-021-00833-8Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science. 2020;367(6477):eaax0182. DOI:10.1126/science.aax0182Corrales L, Gajewski TF. Endogenous and pharmacologic targeting of the STING pathway in cancer immunotherapy. Cytokine. 2016;77:245-7. DOI:10.1016/j.cyto.2015.08.258Jenkins MK. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987;165(2):302-19. DOI:10.1084/jem.165.2.302Yshii LM, Hohlfeld R, Liblau RS. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives. Nat Rev Neurol. 2017;13(12):755-63. DOI:10.1038/nrneurol.2017.144Gibson HM, Hedgcock CJ, Aufiero BM, et al. Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter. J Immunol. 2007;179(6):3831-40. DOI:10.4049/jimmunol.179.6.3831Zheng Y, Josefowicz SZ, Kas A, et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007;445(7130):936-40. DOI:10.1038/nature05563Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201-17. DOI:10.1084/jem.20112741Granier C, De Guillebon E, Blanc C, et al. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open. 2017;2(2):e000213. DOI:10.1136/esmoopen-2017-000213Dalakas MC. Neurological complications of immune checkpoint inhibitors: what happens when you ‘take the brakes off’ the immune system. Ther Adv Neurol Disord. 2018;11:1756286418799864. DOI:10.1177/1756286418799864Kyi C, Carvajal RD, Wolchok JD, Postow MA. Ipilimumab in patients with melanoma and autoimmune disease. J Immunother Cancer. 2014;2(1):35. DOI:10.1186/s40425-014-0035-zSato K, Akamatsu H, Murakami E, et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer. 2018;115:71-4. DOI:10.1016/j.lungcan.2017.11.019Bomze D, Hasan Ali O, Bate A, Flatz L. Association between immune-related adverse events during anti-PD-1 therapy and tumor mutational burden. JAMA Oncol. 2019; 5(11):1633-5. DOI:10.1001/jamaoncol.2019.3221Balachandran VP, Łuksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551(7681):512-6. DOI:10.1038/nature24462Weiss MD, Luciano CA, Semino-Mora C, et al. Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma. Neurology. 1998;51(6):1738-41. DOI:10.1212/wnl.51.6.1738Gerdes LA, Held K, Beltrán E, et al. CTLA4 as immunological checkpoint in the development of multiple sclerosis: CTLA4 and MS. Ann Neurol. 2016;80(2):294-300. DOI:10.1002/ana.24715Wang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(12):1721-8. DOI:10.1001/jamaoncol.2018.3923Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563-80. DOI:10.1038/s41571-019-0218-0Dubey D, David WS, Reynolds KL, et al. Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum. Ann Neurol. 2020;87(5):659-69. DOI:10.1002/ana.25708Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, et al. A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis. Nat Med. 2019;25(8):1243-50. DOI:10.1038/s41591-019-0523-2Johnson DB, Manouchehri A, Haugh AM, et al. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J Immunother Cancer. 2019;7(1):134. DOI:10.1186/s40425-019-0617-xFan S, Ren H, Zhao L, et al. Neurological immune-related adverse events associated with immune checkpoint inhibitors: A review of the literature. Asia Pac J Clin Oncol. 2020;16(6):291-8. DOI:10.1111/ajco.13375Schneider S, Potthast S, Komminoth P, et al. PD-1 checkpoint inhibitor associated autoimmune encephalitis. Case Rep Oncol. 2017;10(2):473-8. DOI:10.1159/000477162Richard K, Weslow J, Porcella SL, Nanjappa S. A case report of steroid responsive nivolumab-induced encephalitis. Cancer Control. 2017;24(5):1073274817729069. DOI:10.1177/1073274817729069Проценко С.А., Антимоник Н.Ю., Баллюзек М.Ф., и др. Практические рекомендации по управлению иммуноопосредованными нежелательными явлениями. Злокачественные опухоли: Практические рекомендации RUSSCO #3s2. 2022;12(3S2-2):203-41 [Procenko SA, Antimonik NJu, Balljuzek MF, et al. Practical Guidelines for the Management of immune-related adverse events. Zlokachestvennie opuholi: Prakticheskie rekomendacii RUSSCO #3s2. 2022;12(3S2-2):203-41 (in Russian)]. DOI:10.18027/2224-5057-2022-12-3s2-203-241Conry RM, Sullivan JC, Nabors LB. Ipilimumab-induced encephalopathy with a reversible splenial lesion. Cancer Immunol Res. 2015;3(6):598-601. DOI:10.1158/2326-6066.CIR-15-0035Salam S, Lavin T, Turan A. Limbic encephalitis following immunotherapy against metastatic malignant melanoma. BMJ Case Rep. 2016;bcr2016215012. DOI:10.1136/bcr-2016-215012Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094-100. DOI:10.1212/WNL.0b013e3182698cd8Leitinger M, Varosanec MV, Pikija S, et al. Fatal necrotizing encephalopathy after treatment with nivolumab for squamous non-small cell lung cancer: case report and review of the literature. Front Immunol. 2018;9:108. DOI:10.3389/fimmu.2018.00108Vitt JR, Kreple C, Mahmood N, et al. Autoimmune pancerebellitis associated with pembrolizumab therapy. Neurology. 2018;91(2):91-3. DOI:10.1212/WNL.0000000000005781Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002;34(8):1154-7. DOI:10.1086/339550