JAK Inhibitors May Reverse Immunotherapy-Induced Diabetes

Immunotherapy-induced type 1 diabetes is a serious side effect faced by some patients receiving treatment for cancer.

However, a team of researchers from the UCLA Health Johnsson Comprehensive Cancer Center has identified a potential means of preventing or this side effect via the use of autoimmune drugs known as JAK inhibitors, it has been announced.

The team, which published its findings in JCI Insight, found in preclinical models that JAK inhibitors could possibly stop autoimmune attacks in insulin-producing cells in the pancreas and may be able to reverse the damage, as detailed in a news release from UCLA.

Dr. Melissa G. Lechner, assistant professor of medicine in the division of endocrinology, diabetes and metabolism at the David Geffen School of Medicine at UCLA and senior author of the study, spoke with CURE about the findings.

Looking forward, Lechner noted that researchers have developed an upcoming five-site clinical trial based on these findings where patients will receive 12 weeks of treatment with the JAK inhibitor Olumiant (baricitinib).

Transcript

So the big question we were trying to answer is: How can we reduce the morbidity and mortality of cancer immunotherapy? I am a physician scientist. I help run the UCLA immunotherapy toxicities team, and I treat many patients who have side effects from cancer immunotherapy, like thyroid damage, or diabetes, and driven from a clinical perspective, I really wanted to be able to offer these patients something when they came to see me in clinic. So we started out with an animal model that mimics the autoimmune side effects we see in cancer immunotherapy, and we had done a prior study looking at the causes of the thyroid inflammation, or thyroiditis, and identified some key autoimmune subsets and a pathway that prevented that autoimmune disease. And we thought maybe a similar pathway was important in the checkpoint inhibitor autoimmune diabetes. And importantly, could we confirm that? And then, did we have a near-term therapy we could offer patients to prevent and reverse the autoimmune diabetes once it developed? So that was kind of our key goals from a clinical standpoint.

We found that there was a clinically approved drug class of medications called Janus kinase (JAK) inhibitors that are used to treat spontaneous autoimmune diseases like rheumatoid arthritis and psoriasis. And we were able to prevent and even reverse some of the autoimmune attack on the pancreas in an animal model of checkpoint inhibitor diabetes. And we further showed that the mechanism by which that was occurring was in part due to blocking of key cytokines, interleukin 21 and interferon gamma, but that we were also able to reduce the numbers and activity of a key autoimmune cell population called T-follicular helper cells, which really across immune related adverse events in different tissues, seem to be a big driver of the autoimmune disease pathogenesis.

References

1. “Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy,” by Dr. Nicole L. Huang et al., JCI Insight.
2. “Common autoimmune drug may help reverse immunotherapy-induced diabetes, UCLA study finds,” by UCLA Health, news release. https://www.uclahealth.org/news/release/common-autoimmune-drug-may-help-reverse-immunotherapy

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