When Ana Luisa Perdigoto, MD, and PhD first joined Dr. Kevan Herold's lab to study type 1 diabetes, the patient was just beginning to develop immune checkpoint inhibitor-induced diabetes. As more people were being treated with this new type of cancer immunotherapy, this side effect has become more common.
“I was very interested in the intersection of endocrinology and immuno-oncology,” says Perdigoto, an assistant professor of medicine (endocrinology and metabolism) at Yale School of Medicine. “So I've shifted to understand checkpoint inhibitor-induced diabetes with the idea that it would also help me understand type 1 diabetes.”
Less than 2% of patients treated with checkpoint inhibitors develop this type of diabetes, but this condition is considered irreversible, says Perdigoto.
The Q&A discusses how this type of immunotherapy can induce diabetes, which patients may be more sensitive, and how her research can try to prevent and treat this life-changing condition.
How can immune checkpoint inhibitor therapy cause diabetes?
Checkpoint inhibitor therapy targets specific proteins called checkpoints on T cells, preventing other cells, such as tumor cells, from binding to partner proteins. This inhibition leads to T cell activation and tumor cell destruction.
These T cells can also target organs in the body. Checkpoint inhibitor therapy has been shown to cause immune-related adverse events in almost all organ systems. Interestingly, some of the more commonly targeted organs are endocrine organs such as the thyroid, pituitary gland, and pancreas. Pancreatic involvement can lead to the form of autoimmune diabetes. When an endocrine organ is attacked, patients usually need to undergo lifelong hormonal therapy, as far as researchers understand.
What type of diabetes can checkpoint inhibitor therapy induce?
I think there are some differences, like type 1 diabetes.
Patients who initiate checkpoint inhibitors often present with very acute and severe hyperglycemia. It's usually very fast. And a significant proportion of patients may present with diabetic ketosidosis, a severe complication that will often result in very little insulin. With this type of diabetes, many patients do not produce their own insulin. And people who usually lose their ability within a few weeks. In contrast, some patients diagnosed with type 1 diabetes can maintain some of their insulin for a long time, sometimes for a long time.
However, checkpoint inhibitor-induced diabetes exists clinically, like type 1 diabetes, as the immune system attacks the beta cells of these patients. It is treated the same as type 1 diabetes.
Why are certain people more susceptible to checkpoint inhibitor-induced diabetes?
One thing I found in collaboration with my oncology colleagues, especially Harriet Kruger, MD, is that a significant proportion of patients who develop this type of diabetes have altered genes called NLRC5. Proteins from this gene regulate immune cells the symptoms of the antigen MHC class 1. These individuals have an improved ability to present pancreatic beta cell antigens to immune cells, making it more susceptible to killing beta cells. This is an area we are currently investigating further.
What is your research goal?
Checkpoint inhibitor-induced diabetes is a complication that can dramatically alter a patient's life. Suddenly, they need to not only deal with advanced cancer, but also constantly monitor their blood sugar levels, take insulin, and see what they eat.
I hope that understanding how this type of diabetes works will lead to my research potentially finding treatments that prevent or reverse it.
Endocrinology and metabolism is one of the 10 sections of Yale Internal Medicine, improving the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. For more information, see Endocrinology and Metabolism.