Checkpoint Inhibitors

Abstract

mmune checkpoint inhibitors activate anti-tumor defenses either through the disruption of inhibitory interactions between antigen-presenting cells and T lymphocytes at so-called checkpoints (anti-PD-1/PD-L1, anti-CTLA-4, anti-TIM-3, anti-LAG-3) or else through the stimulation of activating checkpoints (CD27, CD40, GITR, CD137). They are now used to treat various types of cancer, including lung cancer, renal cell carcinoma, Merkel cell carcinoma, Hodgkin's lymphoma, and urothelial carcinoma (eTable) and special groups of patients, e.g., patients with microsatellite instability (1). In patients with metastatic melanoma, the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and combination therapy with ipilimumab and an anti-PD-1 antibody can prolong survival and induce response rates of 19% (2), 36-44% (2, 3), and 58-61% (2, 4), respectively. Severe and even life-threatening side effects (classified according to the Common Terminology Criteria for Adverse Events" [CTCAE]; grade 3/4) arise in 17-21% of patients receiving anti-PD-1 monotherapy (2, 3), 20-28% of those receiving ipilimumab (2, 3), 45% of those receiving ipilimumab (1 mg/kg) plus pembrolizumab (4), and 59% of those receiving approved combination therapy with ipilimumab (3 mg/kg) and nivolumab (2) (Table 1). Immune checkpoint inhibitors often induce autoimmune side effects, which can affect all organ systems. These differ from the corresponding spontaneously occurring autoimmune diseases in many ways, including phenotypically, histologically, and serologically. The mechanisms of autoimmune side effects include the activation of T lymphocytes with infiltration of the organ in question (5), direct binding of the checkpoint inhibitor with activation of complement (CTLA-4 expression in the pituitary gland) (6), and immune reactions due to soluble factors (autoantibodies, cytokines). Moreover, the intestinal microbiome seems to influence the development of side effects (7, 8). No predictive factors for the appearance of side effects have yet been identified. Common side effects include colitis, hepatitis, skin reactions, and endocrinopathies (thyroiditis or hypophysitis); rarer ones are myositis, cardiomyositis, and neurological side effects. The side effects are usually readily controllable. Checkpoint inhibitor treatment must be discontinued because of side effects in 7-12% of patients receiving anti-PD-1 therapy, 9-16% of those receiving ipilimumab therapy (2, 3), and 39% of those receiving combination therapy (2).

Immune checkpoint inhibitors‐induced neuromuscular toxicity: From pathogenesis to treatment

“…Although, when facing acute neurological symptoms in a patient receiving ICIs, the hypothesis of a neurological irAEs should be immediately evoked, alternative causes (metabolic, endocrine, infectious, and toxic) of neurological dysfunction should be carefully excluded through an appropriate work‐up. Tumor progression and perineural invasion should always be taken into account, as well as the effects of previous anti‐tumoral treatments …”

“…The medical management of pns‐irAEs is complex, as there is a coexistence of an insufficient immune response towards the cancer and an exaggerated immune response towards peripheral nervous system targets . As general considerations, the treatment of pns‐irAEs should be as prompt as possible, with the least possible burden of severe side effects, and without interactions with anti‐tumoral treatments …”

“…High‐dose corticosteroid therapy (commonly, oral prednisone 1 mg/kg/day or an equivalent dose per intravenous route) should be started as soon as possible as it may shorten symptom duration and prevent long‐term sequelae. CTCAE grade 3‐4 toxicities require immediate hospital admission with possible transfer to the intensive care unit . In the event of improvement, corticosteroid can be progressively tapered and discontinued .…”

“…In the event of improvement, corticosteroid can be progressively tapered and discontinued . Nevertheless, given the long half‐life of anti‐CTLA‐4 and anti‐PD‐1 antibodies (3‐4 weeks), maintaining steroid therapy for 2 to 3 months seems reasonable, with appropriate prophylaxis regimens for chronic steroid therapy …”

Nebenwirkungsmanagement bei Immun‐Checkpoint‐Blockade durch CTLA‐4‐ und PD‐1‐Antikörper beim metastasierten Melanom – ein Update

“…Therapeutisch sollte die Thyreoiditis bei symptomatischer Hyperthyreose (Tachykardie) mit Betablockern behandelt werden [2]. Bei manifester Hypothyreose sollte eine Hormonersatztherapie mit Thyroxin erfolgen [2,46]. Die Hypophysitis, die bei 1-7 % der Patienten auftritt, beinhaltet einen kompletten oder partiellen Ausfall der somatotropen, kortikotropen, gonadotropen und thyreotropen Achse des Hypophysenvorderlappens, selten ist auch der Hypophysenhinterlappen betroffen [40,44].…”