Immune Response Checkpoint Inhibitors: New Risks of a New Class of Antitumor Agents

Abstract

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.

Development of destructive thyroiditis and diabetes mellitus after three injections of pembrolizumab for skin melanoma

“…In the clinical case described by us, a hyperergic immune response can be observed, which led to the development of several irAEs with simultaneous manifestation. However, if in the case of vitiligo in melanoma we can talk about the formation of a good response to ICPI (a possible increase in the sensitivity of melanocytes [ 2 ]), and hence an increase in overall and relapse-free survival [ 11 ], the reason for the development of endocrine lesions is unclear. However, such vitilig-like depigmentation differs from classical vitiligo (the latter is localized in photo-exposed areas, and the Kebner phenomenon is observed) [ 12 ].…”

“…In 2018, James P. Allison and Tasuku Honjo were awarded the Nobel Peace Prize in Medicine for their discovery of a fundamentally new approach in the treatment of malignant neoplasms [ 1 ]. The antitumor effect of this type of immunotherapy is realized through blocking the control signaling pathways CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1 (programmed cell death-1 protein) and PD-L1 (programmed cell death receptor ligand-1), which leads to an increase in the antitumor activity of the immune system and is accompanied by an improvement in overall survival rates in a number of tumors [ 2 ].…”

“…All irAEs are described in accordance with the CTCAE (Common Terminology Criteria for Adverse Events) classification from the mild degree (1) to extremely severe (4) and registration of a lethal outcome due to the pronounced irAEs (5) [ 5 ]. Endocrine irAEs of 1–2 degrees are more common [ 2 ].…”

Immunological Approaches to the Treatment of Novel Coronavirus Infection (Review)

“…The COLCORONA study [158] reported that the use of colchicine in outpatients with COVID-19 reduced the risk of hospitalization by 25%, death by 44%, and the need for ventilation by 50%.…”

Endocrine Toxicity of Immune Checkpoint Inhibitors in Clinical Practice

“…Endocrine tissue does not regenerate and has a very small volume, so immune destruction has great consequences for the secretion of major hormones [5]. The development of clinically significant immune mediated adverse reactions may require discontinuing antitumor therapy and prescription of immunosuppressants, so early diagnosis and timely therapy of complications serve as important criteria for successful antitumor therapy [6].…”