The latest cancer immunotherapy has an unintended consequence: insulin-dependent diabetes induced by checkpoint inhibitors (CPI). Early reports suggest that about 1 percent of patients on CPI therapy develop insulin-dependent diabetes and patients with existing type 2 diabetes may suddenly become insulin dependent.
“This is a human experiment in the immunological equilibrium balancing lymphocyte activation and control being done for us,” said Kevan Herold, MD, Professor of Immunobiology and Internal Medicine and Executive Director of the Diabetes Center at Yale School of Medicine.
Dr. Harold explored the emerging problem of CPI-induced diabetes and current attempts to understand its mechanisms of action during Sunday morning’s ADA Diabetes Symposium—Emerging Areas of Islet Biology.
CPIs disrupt the controlled immune response that protects self from attack. The same mechanism of action could be expected to generate immune-related adverse events, Dr. Harold noted.
A growing list of CPIs have been approved or are in development to inhibit cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand-1 (PD-L1). These agents are most commonly used for melanoma, non-small cell lung cancer, renal cell carcinoma, and lymphoma, as well as urothelial, ovarian, head and neck, and hepatocellular cancers.
Beta cells are susceptible to PD-1 and PDL-1 inhibition but not to CTLA-4 inhibition. The mechanisms of beta cell damage are not yet clear.
Diabetes caused by this treatment is usually evidenced by the sudden onset of diabetic ketoacidosis and hospitalization and occurs a mean of 20 weeks into CPI treatment. But the interval ranges from one week to more than 200 weeks, and one cycle of treatment to 78 cycles.
HLA-DR4 (human leukocyte antigen–D-related 4) is associated with CPI-induced diabetes and recovery is uncommon. Early work suggests that some beta cells stressed by inflammatory factors express PD-L1 as a protective measure. That could make them targets for PD-1/PD-L1 inhibition. Work in rheumatoid arthritis suggests that there may be specific genetic factors conferring susceptibility. There may also be cross-reactive epitopes between tumor cells and beta cells.
“There’s potential to block autoimmune response without blocking tumor response,” Dr. Harold said. “Case reports are a good start, but we are desperately lacking in prospective examples. We need multiple centers to collaborate on this.”
Long noncoding RNAs (lncRNA) may be the next frontier in diabetes treatment. This relatively new field of inquiry is moving from basic to translational research, fueled in part by the recognition that lncRNA pathways might be altered using small molecules.
“We are hoping this work leads us in new directions and new understandings of beta cell function and dysfunction,” said Lori Sussel, PhD, Director of Basic and Translational Research at the Barbara Davis Center for Diabetes at the University of Colorado.
LncRNAs are highly tissue-specific and directly regulate transcription factors, Dr. Sussel explained. Her lab has found about 470 lncRNAs in human islet cells. One of them, βlinc1, is islet- and beta cell-specific. Work with knockout mice showed that βlinc1 islets have metabolic defects affecting the maturation and function of beta cells.
Similar work has identified a lncRNA, Paupar, that regulates alpha cell transcription factors. There’s clear potential for the use of small molecule/oligonucleotide mimetics and small molecule inhibitors to modify lncRNA activity, Dr. Sussel said.
“We already see lncRNAs as a novel regulatory component of pancreatic islets,” she added. “LncRNAs could represent novel biomarkers or therapeutic targets for diabetes.”