MRF 25th Anniversary: Managing Immunotherapy-Related Treatment Side Effects

For our 25th anniversary, we share a guest blog from Douglas B. Johnson, MD, MSCI, from Vanderbilt Medical Center and recipient of a research grant provided by the MRF/MRF Breakthrough Consortium: 

“Patient with metastatic melanoma” – these words carried especially grim connotations, even by the difficult standards of oncology when I was a medical student and resident. No consistently effective treatment options had been developed, and patients almost inevitably succumbed to their disease. However, in the 2010s a flurry of progress changed this, and now nearly half of patients with metastatic melanoma experience long-term survival. Although much work remains to be done to improve outcomes for many more patients, immune checkpoint inhibitors have led the way to this sudden transformation.

Immune checkpoint inhibitors were first pioneered in melanoma, and “remove the brakes” on immune cell function. This is particularly helpful in melanoma, where immune responses are often on the verge of breaking through, and simply need the right push from the right treatment to spark long-term anti-tumor responses. However, immune checkpoint inhibitors can also trigger “collateral damage,” where immunity targets a patient’s own body. These autoimmune-like side effects can affect essentially any organ system and happen in an unpredictable fashion. They are now the major limitation to using checkpoint inhibitors more effectively. Our interest in studying these side effects originally started when two patients suddenly developed inflammation of the heart within two weeks of starting therapy and died of this complication. These tragic cases spurred us to gain a deeper understanding.

To address this, along with two other junior investigators, Sunandana Chandra and Meghan Mooradian, I proposed to study these side effects more systematically. Inflammation of the colon, or colitis, caught our attention as a particularly important and problematic side effect. Colitis causes abdominal pain and severe diarrhea, and often forces physicians and patients to stop their treatment. We found the colitis was more common, occurred earlier and was more difficult to treat in patients who received combination immune checkpoint inhibitors. Dr. Mooradian also led an effort and showed that findings on colonoscopy/endoscopy can help determine the best treatment to resolve the colitis.

Though we initially focused on colitis, our work led us to study other side effects as well. We focused on the most severe and rare toxicities – when inflammation caused by checkpoint inhibitors actually led to death. We showed that inflammation of the heart (myocarditis) was the most lethal (though uncommon) side effect, and that severe toxicities usually occurred very early on treatment. This suggested to us that the most dangerous events may have had smoldering inflammation ongoing even before starting treatment that was amplified by immune checkpoint inhibitors. Finally, we performed in-depth study on a patient who developed a fatal case of brain inflammation and found that there may be a link to viral infection with severe toxicities.

Developing a better understanding of immune checkpoint inhibitor toxicities will ultimately allow us to recognize, prevent and treat these side effects better. Perhaps more importantly, it will allow us to treat metastatic melanoma more aggressively and effectively. The grant provided by the MRF/MRF Breakthrough Consortium has allowed us to perform this work and advance the field a little bit further. Importantly, it also provided seed money for us to obtain several large grants from the National Institutes of Health to perform larger and more detailed studies.

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