Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

Abstract

Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs.

A Bloody Conspiracy— Blood Vessels and Immune Cells in the Tumor Microenvironment

“…Finally, immunotherapy has gained much attention over the last few years and holds great promise in oncology. For example, immune checkpoint blockade has appeared as a promising novel strategy in recent years, but its adverse effects still restrict its full clinical potential [ 134 ]. Moreover, CAR (Chimeric Antigen Receptors) T cells have revolutionized the antitumoral immunotherapy field.…”

Understanding the functional inflammatory factors involved in therapeutic response to immune checkpoint inhibitors for pan-cancer

“… Organs susceptible to inflammatory toxicity induced by ICIs. Almost all organs may develop irAEs after receiving ICIs ( Poto et al, 2022 ). Among them, the most common side effects occurred in skin, with an incidence rate of 40%.…”

“…The inflammatory response in rheumatoid arthritis is often accompanied by abundant TNF-α and IL-6 (Mcinnes et al,FIGURE 3 Organs susceptible to inflammatory toxicity induced by ICIs. Almost all organs may develop irAEs after receiving ICIs (Poto et al, 2022). Among them, the most common side effects occurred in skin, with an incidence rate of 40%.…”

“…The number of patients being treated with ICIs is increasing, and thus cases of immune-related adverse events (irAEs) are also reported in a wide range of organs ( June and Bluestone, 2017 ; Poto et al, 2022 ). Although the presence of irAEs is generally believed to be associated with better responses to ICIs, unpredictable and uncontrollable irAEs are a major obstacle preventing a complete course of ICIs therapy.…”

Recent advances, patient selection & challenges in managing cancer patients undergoing treatment with immune checkpoint inhibitors

“…Nevertheless, co-inhibitory ICM-targeted ICMs have side effects related to their lack of specificity, resulting in over-activation of the immune system. These side effects are called immune-related adverse events (IrAEs) and include fatigue, dermatological, gastrointestinal, hepatic, pulmonary, endocrine, ophthalmic, neurological and unusual toxicities such as type 1 diabetes mellitus and cardiac haematological disorders 23 . Dermatological side effects are frequently present and manifest as skin rashes that are often maculopapular and mild 23 .…”