Immune-related Adverse Events in Cancer Patients

Abstract

The U.S. Food and Drug Administration has approved immune checkpoint inhibitors and chimeric antigen receptor T cells (CAR-T cells) as immunotherapy strategies for cancer. These therapies cause a wide variety of adverse events, which mimic other disease states and may emerge months after completion of treatment. This is important because ascertaining a past medical history of cancer treatment within the past year becomes necessary for many presentations. This narrative review summarizes the biology, pathophysiology, and adverse events associated with checkpoint inhibitors and CAR-T cells and provides a rational approach to management. Proper treatment begins with heightened awareness, rapid diagnosis, and discussion with the patient's oncologist. Treatment of these adverse effects requires only corticosteroids, infliximab, tocilizumab, or fluids or vasopressors when clinically indicated.

Figure 1.

Immunologic checkpoints and their inhibition, with representative checkpoint inhibitors. (A) Normal T‐cell activation. The TCR binds to MHC ‐associated antigen, and T cell CD 28 binds to B7 on the tumor cell. The T cell is activated to destroy cells displaying this antigen. (B) CTLA ‐4 is a checkpoint on T‐cell activation. Among several mechanisms of negative immune regulation, CTLA ‐4 outcompetes CD 28 from binding to B7. This reduces T‐cell activation. (C) When PD ‐1 on the T cell binds to PD ‐L1 on the tumor cell, T‐cell activation is inhibited. (D) Monoclonal antibody therapeutics can block the checkpoints depicted in B and C. Ipilimumab is the only approved CTLA ‐4 blocker. The approved PD ‐1 blockers are nivolumab and pembrolizumab; the approved PD ‐L1 blockers are atezolizumab, avelumab, and durvalumab. Ag = antigen; CTLA ‐4 = cytotoxic T‐lymphocyte–associated antigen 4; MHC = major histocompatibility complex; PD ‐1 = programmed cell death protein 1; PD ‐L1 = PD ‐ligand‐1; TCR = T‐cell receptor.

Figure 2:

Time to Onset of Immune-Related Adverse Events Associted with Checkpoint Inhibitor Therapy This figure displays the time to onset of immune-related adverse events after treatment with nivolumab (n=474). Circles represent medians and bars represent ranges; the values are shown above the bars. Included patients were those in Phase III trials. An unspecified number of patients had received prior therapy with ipilimumab. Image used with permission of the publisher.

Figure 3:

Hypophysitis Presenting as Headache and Fatigue after Checkpoint Inhibition A: Baseline brain MRI, demonstrating a normal 4.5 mm pituitary gland (arrow). B: Brain MRI scan of the same patient after he presented with headache and fatigue, demonstrating an inflammed, enlarged 10.8 mm pituitary (arrow). Image used with permission from the publisher.

Figure 4.

Pneumonitis after checkpoint inhibition. Computerized tomography of the chest reveals patchy infiltrates due to autoimmune pneumonitis associated with checkpoint inhibitor therapy. Image courtesy of coauthor Michael Postow.