S.Z. Safina ¹, G.K. Mukhamed’yarova ¹, V.V. Dimitrieva ¹

1. «State Autonomous Institution of Health «Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan», Kazan, Russian Federation

DOI: https://www.doi.org/10.52532/2521-6414-2023-2-68-59-63

UDC: 616.43-006

Year: 2023 issure: 68 number: 2 pages: 59-63

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ABSTRACT

Relevance: Immunological control points significantly changed cancer therapy worldwide after a new class of inhibitor drugs was registered. Based on clinical studies, this type of treatment was associated with better survival in sensitive patients than cytostatic therapy. Checkpoint inhibitors exert their effect by regulating the immune response to malignant cells, blocking the usual inhibitory pathways of T-cell regulation. The receptors of cytotoxic T-lymphocytic antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its associated ligand (PD-L-1) are the target of inhibitors. CTLA-4 acts at an early stage of triggering an antigenic response, and PD-1 and PD-L-1 act by modulating interaction with peripheral tissue
However, treatment with checkpoint inhibitors (ICTs) is accompanied by a wide range of immune mediated adverse events associated with the activation of the immune system. Despite the positive effect on survival, side effects with endocrine effects were noted in about 10% of patients.
The study aimed to assess the incidence of immune mediated adverse events from the thyroid gland in clinical practice in patients with different localization of malignant tumors in the first and subsequent lines of therapy with checkpoint inhibitors.
Methods: The study utilized anamnestic, laboratory, and instrumental tests. Laboratory analysis included determining the blood levels of TSH, T3, T4, ACTH, and cortisol. Data analysis was carried out using the Microsoft Excel program.
Results: The frequency of development of immune mediated thyroiditis against the background of therapy with blockers of control points of the immune pathway in our observation was 29%. The debut of thyroid disorders was diagnosed in the first 12-16 weeks of therapy, beginning with hyperthyroidism against the background of thyroid destruction, followed by a transition to persistent hypothyroidism after 1-3 months.
Conclusion: When analyzing the safety profile of ICTs in patients in our study, immune mediated adverse reactions did not differ in frequency and spectrum from world practice. The spectrum of toxicity did not depend on the localization of the tumor. Early diagnosis of thyroid lesions necessary for optimal and effective treatment can be carried out using laboratory tests. Knowing the timing of the development of adverse events during ICT therapy allows timely diagnosing and correcting complications from the thyroid to continue effective therapy.
Keywords: immune mediated endocrinopathy, immunotherapy, checkpoint inhibitors (ICTs).

List of sources used:

1. Нуралиева Н.Ф., Трошина Е.А., Мельниченко Г.А. Поражение желез внутренней секреции как осложнение иммунотерапии в практике онколога // Клин. Эксперимент. Тиреоидология. – 2018. – №14 (4). – С. 174-182 [Nuralieva N.F., Troshina E.A., Mel’nichenko G.A. Porazhenie zhelez vnutrennej sekrecii kak oslozhnenie immunoterapii v praktike onkologa // Klin. E’ksperiment. Tireoidologiya. – 2018. – №14 (4). – S. 174-182 (in Russ.)]. https://doi.org/10.14341/ket9875
2. Yamauchi I., Sakane Y., Fukuda Y., Fujii T., Taura D, Hirata M., Hirota K., Ueda Y., Kanai Y., Y., Kondo E., Sone M., Yasoda A., Inagaki N. Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study // Thyroid. – 2017. – Vol. 27 (7). – P. 894-901. https://doi.org/10.1089/thy.2016.0562
3. Журтова И.Б., Эльгарова Л.В., Губачикова А.М. Иммуноопосредованные нежелательные эндокринные явления при лечении ингибиторами контрольных точек иммунного ответа: клинический случай ниволумаб-индуцированного тиреоидита // Фарматека. – 2022. – Т. 29, № 7. – С. 90-94 [Zhurtova I.B., E’l’garova L.V., Gubachikova A.M. Immunooposredovannye nezhelatel’nye e’ndokrinnye yavleniya pri lechenii ingibitorami kontrol’nyx tochek immunnogo otveta: klinicheskij sluchaj nivolumab-inducirovannogo tireoidita // Farmateka. – 2022. – T. 29, № 7. – S. 90-94 (in Russ.)]. https://dx.doi.org/10.18565/pharmateca.2022.7.90-94
4. Sznol M., Postow M. A,. Davies M. J., Pavlick A.C., Plimack E. R., Shaheen M., Veloski C., Robert C. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management // Cancer Treat. Rev. –2017. – Vol. 58. – P. 70-76. https://doi.org/10.1016/j.ctrv.2017.06.002
5. Higham C.E., Olsson-Brown A., Carroll P., Cooksley T., Larkin J, Lorigan P., Morganstein D., Trainer P. J., the Society for Endocrinology Clinical Committee. Society for Endocrinology Endocrine Emergency Guidance: Acute management of the endocrine complications of checkpoint inhibitor therapy // Endocrine Connect. – 2018. – Vol. 7(7). – P. G1-G7. https://doi.org/10.1530/EC-18-0068
6. Шубникова Е.В., Букатина Т.М., Вельц Н.Ю., Каперко Д.А., Кутехова Г.В. Ингибиторы контрольных точек иммунного ответа: новые риски нового класса противоопухолевых средств // Безопасность и риск фармакотер. – 2020. – Т. 8, № 1. – С. 9-22 [Shubnikova E.V., Bukatina T.M., Vel’c N.Yu., Kaperko D.A., Kutexova G.V. Ingibitory kontrol’nyx tochek immunnogo otveta: novye riski novogo klassa protivoopuxolevyx sredstv // Bezopasnost’ i risk farmakoter. – 2020. – T. 8, № 1. – S. 9-22 (in Russ.)]. https://doi.org/10.30895/2312-7821-2020-8-1-9-22
7. Faje A.T , Sullivan R., Lawrence D., Tritos N. A., Fadden R., Klibanski A., Nachtigall L. Ipilimumab-Induced Hypophysitis: A Detailed Longitudinal Analysis in a Large Cohort of Patients With Metastatic Melanoma // J. Clin. Endocrinol. Metabol. – 2014. – Vol. 99 (11). – P. 4078-4085. https://doi.org/10.1210/jc.2014-2306
8. Hattersley R., Nana M., Lansdown A.J. Endocrine complications of immunotherapies: a review // Clin. Med. J. – 2021. – Vol. 21 (2). – P. e212-e222. https://doi.org/10.7861/clinmed.2020-0827
9. Paschou S.A., Stefanaki K., Psaltopoulou T., Liontos M., Koutsoukos K., Zagouri F., Lambrinoudaki I., Dimopoulos M.-A. How we treat endocrine complications of immune checkpoint inhibitors // ESMO Open. – 2021. – Vol. 6 (1). – Art. no. 100011. https://doi.org/10.1016/j.esmoop.2020.100011
10. IshidaY., Agata Y., Shibahara K., Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death // EMBO J. – 1992. – Vol. 11. – P. 3887-3895. https://doi.org/10.1002/j.1460-2075.1992.tb05481.x
11. Chang L.-S., Barroso-Sousa R., Tolaney S.M.,Hodi S.F.,Kaiser U.B., Min L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints // Endocrine Rev. – 2019. – Vol. 40 (1). – P. 17-65. https://doi.org/10.1210/er.2018-00006
12. Agrawal L., Bacal A., Jain S., Singh V., Emanuele N., Emanuele M., Meah F. Immune checkpoint inhibitors and endocrine side effects: a narrative review // Postgrad. Med. – 2020. – Vol. 132 (2). – P. 206-214. https://doi.org/10.1080/00325481.2019.1709344