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.

Fig. 1. Proposed mechanisms of immune-related adverse events.

Schema depicting the interaction of T cells with malignant or non-malignant cells, and the molecular mechanisms of immune-checkpoint blockade. Tumour-specific (left) and non-tumour-specific (right) aspects associated with the development of irAEs are also included. ADCC, antibody-dependent cellular cytotoxicity; NK cell, natural killer cell; TCR, T cell receptor.

Fig. 2. Mechanisms of chronic immune-checkpoint inhibitor-mediated toxicity.

a | Smouldering toxicities characterized by off-target T cell activation that may wax and wane over time. Examples include rheumatoid arthritis-like inflammation of the joints. Such effects often resolve on treatment withdrawal and/or steroids b, c | Burnout toxicities characterized by irreversible damage to the relevant cells, typified by immune-checkpoint inhibitor-mediated endocrinopathies. Examples include destruction of the hormone-secreting cells of the pancreas (b) or thyroid (c). Such toxicities are usually irreversible and require permanent hormone-replacement therapy.

Fig. 3. Possible frequencies of chronic immune-checkpoint inhibitor-induced toxicities.

The exact risks of acute toxicities becoming chronic (defined as persisting for at least 12 weeks beyond treatment cessation) are currently unknown, although endocrinopathies, arthritis, xerostomia, neurotoxicities and ocular events are generally more likely to become chronic toxicities. Immune-related adverse events affecting the visceral organs seem to have a lower risk of becoming chronic. Percentages expressed are the percentages of acute toxicities that become chronic (defined as those that persist for at least 12 weeks following immune-checkpoint inhibitor discontinuation) from ref..

Fig. 4. Time course and potential importance of key issues throughout the course of treatment with immune-checkpoint inhibitors.

The relevant time frame of important patient-specific/toxicity-related factors (top), includes acute toxicities, which are largely relevant while patients are on therapy, chronic toxicities, which probably slowly decline over time, and the potential (theoretical) effects of such toxicities on other immune processes such as atherosclerosis, which could increase over time. Tumour-specific factors, including the risks of recurrence and the need for rechallenge, both of which appear to decrease over time are depicted below the timeline. ICI, immune-checkpoint inhibitor.