Averting and Treating Immune-related Adverse Events Associated with Checkpoint Immunotherapies

The first ever immune checkpoint inhibitor was approved by the Food & Drug Administration (FDA) in 2011 with an indication for treating metastatic melanoma. That approval was built upon ground-breaking research by Jim Allison, MRA Scientific Advisory Panel member and 2018 Nobel Laureate. Since then, additional immune checkpoint therapies have been approved for melanoma. Indeed, checkpoint inhibitors have not only dramatically improved health outcomes in melanoma,but are now being used to treat over a dozen different cancers.

Checkpoint inhibitors are therapies that empower the immune system to kill cancer cells. FDA-approved checkpoint immunotherapies block specific proteins on both immune cells (PD1, CTLA4) and sometimes the tumor (PDL1) that normally act as “off” switches for the immune system. This then releases the breaks on immune cells, allowing them to kill tumor cells. While this approach has yielded dramatic results in resolving numerous cancers, sometimes immune-related adverse events (irAE) can also occur as a result of the immune system attacking healthy tissues. Such autoimmune reactions can hamper patients’ quality of life, can limit the effectiveness of the treatments by requiring treatment discontinuation, and in rare instances can be fatal.

To help overcome this challenge, MRA has issued a number of research grants, including some in partnership with the American Cancer Society (ACS) and the Society for Immunotherapy of Cancer (SITC), to support an array of approaches. Some are exploring what causes these severe adverse reactions and treatments that might prevent or reverse them. Others are devising new experimental drugs that have the same tumor-killing effects as approved therapies, but without the autoimmune side effects. Another group is searching for molecular markers that can predict which patients are more likely to develop adverse reactions to currently approved immunotherapies, which would help doctors select the best possible treatment for each patient. These investigators reported on their exciting findings at the MRA 2021 Scientific Retreat.

Treating Colitis Among Patients Receiving Checkpoint Immunotherapy

Kai Wucherpfennig of Dana-Farber Cancer Institute and his colleagues used their MRA-American Cancer Society Team Science award to explore what goes awry in melanoma patients who develop colitis after being treated with checkpoint inhibitors. Colitis, inflammation of the colon that causes severe diarrhea, is a common irAE affecting up to 25% of patients receiving checkpoint immunotherapy.

When Wucherpfennig compared colon tissue samples of patients who developed colitis to those being treated with the same therapies who did not develop colitis, he found key molecular differences. These changes included an increase in a protein called tumor necrosis factor (TNF) in those with colitis, suggesting that a drug already on the market that targets this factor (infliximab) might alleviate this complication. Team member Michael Dougan, of Mass General, initiated a clinical trial that opened in August 2020 to test this possibility (NCT04305145). Wucherpfenning noted that although his findings are specific to the colitis, some of the molecular changes he observed are likely to be relevant for other irAEs affecting the skin, lungs, and other tissues that frequently interact with microbes in the environment.

The Next Generation of CTLA4 Checkpoint Immunotherapies

Pan Zheng, formerly of University of Maryland, Baltimore, and founder of the biotech companies OncoImmune and OncoC4, is hoping to avoid autoimmune side effects with next generation anti-CTLA-4 antibodies that are being tested in the clinic. Her studies in mice found some antibodies targeting the protein CTLA-4 were able to effectively kill melanoma tumors without triggering an autoimmune reaction, unlike the current CTLA-4 targeted therapy (ipilimumab). She and her team hope that these alternative antibodies could serve as a second generation CTLA-4 therapy and would allow patients to experience the tumor-killing effects of the therapy while minimizing the irAEs.

Zheng then investigated why this was the case and found that CTLA4 protein bound to ipilimumab was broken down in immune cells, which reduced the amount of CTLA4 expressed on the surface of these cells. In contrast, the new antibody Zheng developed maintained the level of CTLA4 on the cell surface. In the case of Zheng’s antibody, this difference allowed the mice to better keep autoimmune reactions at bay. “Our findings suggest autoimmune disease is not necessarily the price for cancer immunity,” Zheng said. “You can have an anti- tumor effect without immune-related adverse events.” With the support of a National Cancer Institute small business innovation award, Zheng is currently testing one of these antibodies (ONC-392) in a small number of cancer patients either alone, or in combination with pembrolizumab, to determine its safety and optimal dosing for future clinical trials (NCT04140526).

Predicting Patients Most Likely to Develop Serious Reactions

Another approach to avoiding serious autoimmune reactions of cancer immunotherapies is to predict those patients who are more likely to develop them. MRA-SITC Young Investigator Shaheen Khan of UT Southwestern and her colleagues have discovered molecular markers that show promise for identifying these patients. Certain protein levels were increased in blood samples taken from cancer patients, including patients with melanoma, who experienced autoimmune reactions to checkpoint immunotherapy compared to those that did not. If these findings are validated in future studies, clinicians could use them to help inform treatment decisions and to identify irAEs in their earliest stages, when they may be more easily treated.

The researchers also developed mice who are prone to autoimmune disease as a model for studying irAEs, and found one of the proteins detected in cancer patients who develop autoimmune reactions was also elevated in the autoimmune-prone mice. Studies in these mice might suggest ways to prevent the autoimmune reactions from occurring in patients altogether. “We hope our findings may ultimately help customize therapy, expand the use of immunotherapy, and reduce toxicities in cancer patients,” Khan noted in a poster session.