A team of researchers at the UCLA Health Jonsson Comprehensive Cancer Center has identified a potential new strategy to prevent, and even reverse, immune checkpoint inhibitor–induced type 1 diabetes, a rare but life-threatening side effect of cancer immunotherapy, using an existing class of autoimmune drugs.
The study , published in JCI Insight, identifies a new group of immune cells involved in the development immune checkpoint inhibitor–induced type 1 diabetes and shows that JAK inhibitors, which are already FDA-approved for conditions like psoriasis and arthritis, can stop the autoimmune attack on insulin-producing cells in the pancreas and, in some cases, even reverse the damage in preclinical models.
The findings point to a new way to protect patients from this serious endocrine-related complication of cancer immunotherapy — one that currently has no effective way to prevent or reverse its effects — without compromising the effectiveness of their cancer treatment.
"This is one of the first times we've found a way to intervene in these toxicities in a meaningful way," said Dr. Melissa 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. "As more patients receive immunotherapy for early-stage and potentially curable cancers, preventing long-term autoimmune damage is becoming a critical part of survivorship care. This study brings us closer to protecting patients without compromising the life-saving benefits of their treatment."
Checkpoint inhibitors like pembrolizumab and nivolumab have revolutionized cancer treatment by activating the immune system to attack tumors, but they can also cause serious autoimmune side effects. More than two-thirds of patients who receive these therapies experience some form of immune-related toxicity. While rare, one of the most severe is type 1 diabetes, which affects 1% to 2% of patients and is often permanent. Nearly 90% of those who develop it require ICU care for life-threatening complications and are left insulin-dependent for life.
To better understand the mechanisms underlying this type of type 1 diabetes that is triggered by immune checkpoint inhibitors, Lechner and her team analyzed immune responses in mice models to see if they could identify the immune cell populations responsible for this toxicity.
While past research has primarily focused on CD8+ T cells, the team discovered that a previously unrecognized population of immune cells called CD4+ T follicular helper (Tfh) cells plays a major role in driving the aggressive autoimmune attack on insulin-producing beta cells in the pancreas during cancer immunotherapy. These cells produce two key signaling molecules, IL-21 and interferon gamma (IFNγ), which fuel the immune attack on the pancreas.
The team then tested whether JAK inhibitors, which block the IL-21 and IFNγ pathways, could prevent the onset of immune checkpoint inhibitor–induced type 1 diabetes in mice.
They found the treatment not only blocked the effects of IL-21 and IFNγ, but they were able to reduce the number of Tfh cells and, in some cases, restore normal blood sugar levels, suggesting the potential to not only prevent but also reverse the disease.
"This is the first study to identify Tfh cells and the IL-21/IFNγ pathway as key drivers of checkpoint inhibitor–induced type 1 diabetes," said Lechner. "Importantly, we show that this pathway can be therapeutically targeted with a drug that is already FDA-approved and widely available without weakening the immune system's ability to fight cancer."
The group had also previously shown that the same cell population was involved in thyroid toxicities from checkpoint inhibitors, suggesting a shared mechanism across multiple autoimmune side effects.
"These CD4+ T cells seem to play a common role in different autoimmune toxicities," said Lechner. They could even potentially be used as a predictive biomarker to identify at-risk patients before symptoms start."
The team is now working to launch a first-in-human clinical trial to test the approach in patients with cancer who develop diabetes after immunotherapy.
"If we can make immunotherapy safer, especially for patients with pre-existing autoimmune disease who are often excluded from trials, we can extend the reach of these therapies," Lechner said. "And we can start to offer real solutions to the thousands of patients living with permanent side effects."
The study's first authors are Nicole Huang, a staff research associate at the David Geffen School of Medicine at UCLA, and Jessica Ortega, a medical student at the University of California, San Francisco. Other UCLA authors are Kyleigh Kimbrell, Joah Lee, Esther Peluso, Sarah Wang, Kristy Kim, Jarold Olay, Jaden Nguyen and Maureen Su. A full list of collaborating authors can be found here .
The work is part of UCLA's Autoimmunity Center of Excellence , a collaboration with the National Institute of Allergy and Infectious Diseases aimed at discovering innovative treatments for autoimmune diseases.
The study was funded in part by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, the Aramont Charitable Foundation and the Parker Institute for Cancer Immunotherapy.
