Immune-checkpoint inhibitors: long-term implications of toxicity

Abstract

The development of immune-checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease, and providing new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued. Nonetheless, emerging evidence indicates that persistent toxicities might be more common than initially suggested. While generally low-grade, these chronic sequelae can affect the endocrine, rheumatological, pulmonary, neurological and other organ systems. Fatal toxicities also comprise a diverse set of clinical manifestations and can occur in 0.4–1.2% of patients. This risk is a particularly relevant consideration in light of the possibility of long-term survival. Finally, the effects of immune-checkpoint blockade on a diverse range of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity and hypertension, have not been characterized but remain an important area of research with potential relevance to cancer survivors. In this Review, we describe the current evidence for chronic immune toxicities and the long-term implications of these effects for patients receiving ICIs.

Emerging Therapies for Hepatocellular Carcinoma (HCC)

“…AE of grade 3 or more was observed in 71% patients, most common being hypertension (17%), with three patients dying during treatment. One of the consequences of ICI treatment is adverse effects, including the development of autoimmunity because of augmented immune activity [ 106 ]. Nevertheless, combination immunotherapy seems to become the treatment of choice for all HCC patients, and the completion of the ongoing Phase 3 trials will provide further rationale in this context.…”

Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

“…However, increasing evidences indicate that chronic irAEs are more prevalent than originally recognized ( 46 , 47 ). Endocrinopathies (such as ICI-induced hypothyroidism and diabetes) and rheumatological toxicities (such as arthritis) are the most common chronic irAEs ( 48 , 49 ). Endocrinopathies provide classical examples of irreversible damage of the relevant hormone-secreting cells.…”

“…Colitis occurs more commonly with ipilimumab and with combined immune checkpoint blockade than with anti-PD-1/PD-L1 alone ( 112 , 120 ). Endocrinopathies (such as hypothyroidism, hypophysitis, and adrenal insufficiency) and rheumatological disorders have the highest incidence of development into subacute/chronic toxicity ( 49 ). Endocrine toxicities, unlike many other irAEs, are not managed using high-dose glucocorticoids, which have no effect on either initial severity and resolution ( 121 , 122 ).…”

“…Endocrine toxicities, unlike many other irAEs, are not managed using high-dose glucocorticoids, which have no effect on either initial severity and resolution ( 121 , 122 ). Although acute myocarditis was the first cardiovascular irAEs associated with ICIs ( 123 ), an important unanswered question relates to the long-term cardiovascular sequelae of ICIs ( 49 , 56 , 57 ).…”

Immune Checkpoint Activity Regulates Polycystic Kidney Disease Progression

“…Immune checkpoints, such as programmed cell death protein 1|programmed cell death ligand 1 (PD-1|PD-L1), are proteins that regulate immune homeostasis, prevent excessive CD8 + T cell activation, and protect against autoimmunity (27). Tumors have exploited this pathway to escape immune surveillance.…”