What Specialists Need to Know About Immune-related Adverse Events From Cancer Immunotherapy

Checkpoint inhibitors (CPI) have revolutionized the treatment of various cancers but are known to cause immune-related adverse events (irAEs). At the virtual Interdisciplinary Autoimmune Summit 2020, Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic Learner College of Medicine in Cleveland, Ohio, discussed common irAEs and the importance of a multidisciplinary approach to treat these patients.¹

In acute infections, the innate immune system is deployed to remove the offending microbe, virus, etc. After 96 hours, this response becomes overwhelmed and an adaptive immune response is generated to responded to the threat. Several mechanisms activate antigens, T cells, and cytokines to attack, for example the common cold virus, in the absence of causing damage to the host.

In chronic infections and tumors, antigens are still expressed and a small immune response still generates neoantigens. This causes checkpoints, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1), to produce exhausted T cells that do not secret as many inflammatory cytokines.

“We should not be surprised that CPIs cause irAEs,” said Dr Calabrese. Preclinical models showed a wide variety of autoimmune toxicities from knocking out CTLA4 and PD-1, and also two primary immune deficiencies in humans related to CTLA4.

Dr Calabrese quoted June et al’s 2017 article from Nature Medicine that explored how autoimmunity may be the Achilles heel for immunotherapies, despite their use exploding in cancer treatments.² No organ system is spared from these events, with up to 43% of patients treated with high dose anti-CTLA4 and up to 20% of patients treated with PD-1 therapies experience grade 3 irAEs.

“These are not rare events,” Dr Calabrese reiterated. “We know that combination therapy is more toxic than CTLA4 therapy alone and that is more toxic than PD-1/PD-L1 therapies.” In addition, it appears that the incidence of irAEs are dose dependent and related to the duration of exposure. However, some patients can develop these events with only one or two doses.

“Most importantly, and I shout this as an interprofessional cry,” said Dr Calabrese, “you may be seeing this patient because they have colitis but there is a 50% chance that they will develop another irAE.”

The skin is the most common organ involved in irAEs, which can range from benign conditions to grade 4 diseases. Gastrointestinal organs are also heavily involved, and 1% to 2% of these can be grade 3 or 4 and fatal, he added. Inflammatory arthritis is distinctive because up to 40% of patients after 6 months and up to 25% of patients after 2 years of discontinuation of treatment can still develop this irAE, he said. While myocarditis is rare, it accounts for the majorities of fatalities, noted Dr Calabrese. 

Patients with underlying autoimmune diseases need to be seen by specialists upfront because a third will experience a relapse and just as many will develop a second irAE, he added. However, autoimmune diseases are not contraindications for CPIs.

“This is a team sport and these patients need to be seen in days,” Dr Calabrese reemphasized at the end of his presentation.

For more coverage of IAS 2020, visit the newsroom.

—Melissa Weiss

References

1. Calabrese L. The emerging field of immune related adverse events from cancer immunotherapy: challenges for the non-oncologist. Presented virtually at: Interdisciplinary Autoimmune Summit 2020; July 11, 2020.

2. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med. 2017;23(5):540-547. doi:10.1038/nm.4321