Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination

Abstract

Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors

“…Immune checkpoint inhibitors (Table 1) Use of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD1) and its ligand (PDL-1) inhibitors, either as single agents or in combination, results in a distinct spectrum of toxicities, mostly related to activation of the immune system [168]. Among the multiple IRae reported with these drugs, dermatologic toxicities represent the most frequent adverse events [19,20,168].…”

Early B cell changes predict autoimmunity following combination immune checkpoint blockade

“…Unfortunately, CCB therapy is associated with a significant increase in immune-related adverse events (IRAEs) including treatmentrelated grade 3 or higher IRAEs in over half the patients, leading to discontinuation of therapy in approximately 40% of patients (2,3). Development of IRAEs is therefore a major obstacle to the optimal application and evaluation of CCB therapy (3).…”

Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+T cell trafficking

“…Function-blocking antibodies against CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) enhance anti-tumor T cell responses and result in durable antitumor activity across most cancers (6,7). In melanoma, the anti-PD-1/anti-CTLA-4 combination therapy showed a superior efficacy as compared to the two monotherapies (8), and has been approved in various countries (9). Despite numerous studies on anti-PD-1 and anti-CTLA-4 in melanoma, very limited data are available for BrM, mainly due to frequent exclusion of patients with BrM from clinical trials (4,10).…”