Dr. Melissa G. Lechner

Existing autoimmune drugs may prevent or reverse a serious side effect faced by patients with cancer.

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 

, 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.

 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).

What was the clinical question or unmet need that inspired your research into immune-related adverse events from cancer immunotherapy, and how did you approach investigating it?

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.

“Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy,” by Dr. Nicole L. Huang et al., 

“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

Transcript has been edited for clarity and conciseness.

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CURE spoke with an expert to learn what patients need to know about immunotherapy-induced diabetes.

What Is Immunotherapy-Induced Diabetes?

Among patients with cancer, treatment with immunotherapies — a type of drug that helps to activate the immune system to fight cancer — can also result in unwanted attacks on healthy tissues known as autoimmune diseases, as an expert explained in an interview with CURE.

Dr. Melissa G,. Lechner, assistant professor of medicine in the division of endocrinology, diabetes and metabolism at the David Geffen School of Medicine, spoke with CURE about one of these side effects: immunotherapy-induced diabetes.

Lechner is the senior author of a study published in 

 that identifies JAK inhibitors as a potential means of preventing and possibly reversing immune checkpoint inhibitor-induced type 1 diabetes.

What should patients and clinicians know about the potential autoimmune side effects of immunotherapy, particularly how it can impact metabolic health, such as triggering diabetes?

Immunotherapies help activate the immune system to fight cancer. Because they activate the immune system, they can have unwanted attacks on healthy tissues that we think of as autoimmune disease, which can affect a number of different tissues. About two-thirds of patients get it. In particular, checkpoint inhibitor immunotherapy can cause diabetes, which is an accelerated form of autoimmune diabetes that happens in about 1% of patients who receive cancer immunotherapy.

I think our patients with cancer are obviously facing a lot of different comorbid health problems, and it's helpful to distinguish them. We certainly see a lot of patients who have diabetes from the type 2 insulin resistance form, but we also have a lot of patients who get these autoimmune side effects. I think it's also helpful to put it in context with spontaneous type 1 diabetes.

People are familiar with juvenile diabetes, or spontaneous type 1 diabetes, which is an autoimmune attack on the pancreas's insulin-producing cells that can happen over a period of months to years. In contrast, the immune checkpoint inhibitor form of autoimmune diabetes is an autoimmune attack. It similarly destroys all of the insulin-producing cells in the pancreas and leads to a complete dependence on multiple daily injections of insulin. However, in contrast to juvenile type 1 diabetes, it tends to progress over a period of weeks.

Patients very rapidly have high blood sugar, and it's so rapid and aggressive that about 80% to 90% of those patients will have diabetic ketoacidosis, which is a very severe form of hyperglycemia and insulin deficit that actually lands them in the intensive care unit at diagnosis. So, it's a very rapid form of the disease and is considered almost universally permanent. You have a very dangerous and debilitating diagnosis that is added to a patient with cancer's already challenging regimen in many cases.

Dr. Melissa G. Lechner

JAK Inhibitors May Reverse Immunotherapy-Induced Diabetes

What Is Immunotherapy-Induced Diabetes?

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