Immune Checkpoint Inhibitor-Induced Type 1 Diabetes

The onset of a new form of autoimmune, insulin-dependent diabetes are among the possible adverse events requiring vigilance to detect and manage as more patients receive monoclonal antibody therapy for cancer.

With Kevan C. Herold, MD, and Priyathama Vellanki, MD

The increasing number of patients with endocrine-related conditions who are currently under treatment or have been treated with immune checkpoint inhibitors (ICI), introduces the need to recognize and manage the development of any potential toxicity side effects that may arise.1

Use of immune-therapy anti-cancer drugs has become more common as the treatment of choice for several forms of cancer, such as head and neck cancer, melanoma, and bladder cancer.1  While effective in addressing the cancers, serious adverse events may arise slowly and insidiously, affecting hormone-producing organs (ie, thyroid gland, pancreas). 

Of particular concern is the development of a form of insulin-dependent diabetes that has begun to appear in individuals treated with checkpoint inhibitor blockade. This observation prompted a team of researchers from Yale University and the University of California at San Francisco to examine the features that may lead to checkpoint inhibitor-induced (CPI) diabetes.2

Tracking Patients Treated with Checkpoint Inhibition Therapy

In this two-site study,2 the researchers identified all cases of insulin-dependent diabetes that occurred at two academic institutions over a six-year period in patients who received treatment with ICIs. There were 27 patients (out of a total of 2,960) who exhibited solid-organ cancers and received treatment with either anti-PD-1 or anti-PD-L1 antibodies, which resulted in an incidence rate of insulin-dependent diabetes of about 0.9%.2

Of the patients who were treated with checkpoint inhibition blockade for their cancer, five of them had a personal history of prediabetes, two were diagnosed with type 2 diabetes, and 30% of the remaining patients had a personal history of other autoimmune diseases.2

While most of the patients identified as developing ICI-induced diabetes had malignant melanoma, the authors suggest that this may be explained because the use of ICI drug was initially tested in patients with this form of skin disease. Therefore, use of ICI for other cancers was introduced more recently, influencing the number of prospective patients to be followed.

One of the More Prevalent ICI Side Effects Was Diabetic Ketoacidosis

More than half of the patients (59%; 16 out of 27) presented with acute diabetic ketoacidosis (DKA). However, their average hemoglobin A1c (HbA1c) was 7.95% (63 mmol/mol) at diagnosis, indicating possible prior hyperglycemia.2  The researchers noted that the majority of patients (85%) had a rapid loss of β cell function.2 Nearly half (42%) of the ICI-treated patients had evidence of pancreatitis before diagnosis. At least one autoantibody was measured in 25 of the 27 patients.

In 76% of these patients, the gene serotype—HLA-DR4—was present. In contrast, none of the patients without a diagnosis of diabetes had more than one positive autoantibody,2 as reported by the researchers.

Further investigation found that many of the patients involved in this study who developed checkpoint-inhibitor induced diabetes had manifestations that were more similar to type 1 than to type 2 diabetes. In fact, 40% of patients had at least 1 antibody that was positive and commonly found in spontaneous type 1 diabetes. More than 1 in 5 had 2 or more autoantibodies that were positive. Further, the average insulin dosage at first follow-up visit was 0.56 units/kg/day, suggesting insulin sensitivity more consistent with type 1 vs type 2 diabetes.

In an interview with EndocrineWeb, senior study author, Kevan C. Herold, MD, professor of immunobiology and medicine, and director of the Center for Clinical Investigation at Yale School of Medicine in New Haven, Connecticut, who was one of the authors of the study, said: “many community-based endocrinologists may not be very aware of this disease; however, as ICIs are being used more frequently and in more types of cancers, it is likely they will be seeing an increasing number of these patients.”  

Also, while CPI-induced diabetes is seemingly rare, checkpoint inhibibor-induced thyroid disorders may affect more than 10% of patients treated with these agents, Dr. Herold said. “Because these patients lose their ability to make beta cells very quickly, many will require insulin therapy for the rest of their lives.”

Priyathama Vellanki, MD, assistant professor in the Division of Endocrinology, Metabolism and Lipids at Emory University School of Medicine in Atlanta, Georgia, emphasized that “every patient receiving CPIs needs to be educated regarding the symptoms of DKA: polyuria and polydipsia, and how to check their blood glucose levels.”

Dr. Herold pointed out that treatment with different CPIs seems to target different endocrine disorders. Specifically, CPI-induced diabetes appears to be specifically related to anti-PD-1 or PD-L1 therapies, whereas thyroid disorders are more frequent with anti-PD-1/L1 mAbs than anti-CTLA-4 mAbs. Combination therapies are more likely to result in endocrine adverse events than monotherapies.

Therapeutic Role and Clinical Use of Immune Checkpoint Inhibitors

The use of immune checkpoint inhibitors to treat cancers deemed resistant to conventional chemotherapy and radiation therapies has been substantially expanded over the past few years. These monoclonal antibodies blocker immune inhibitory ligands: CTLA-4 and PD-1. Treatment with CPIs has led to significant improvements in life expectancy among patients with a range of malignancies, including melanoma, lung cancer, and renal cell carcinoma.

The CTLA-4 and PD-1 immune checkpoints inhibitors are instrumental in maintaining immune tolerance through negative regulation of the immune system.2 The CTLA-4 is present in naïve T-cells in lymph tissue and in regulatory T-cells, and binds to CD80/96 on antigen-presenting cells, which leads to inhibition of the immune T-cell response.

Similarly, binding of PD-1 to its ligands PD-L1 and PD-L2 promotes inhibition of the immune response via action in peripheral tissues. The CPIs reverse the mechanisms that otherwise block immune responses to malignancy, and maintain control of antitumor immunity.2

Current CPIs include the anti-CTLA-4 mAb ipilimumab; the anti-PD-1 mAbs nivolumab and pembrolizumab; and the anti-PD-L1 mAbs atezolizumab, avelumab and durvalumab. Tremelimumab, another anti-CTLA-4 mAb, is currently in trials. The CPIs allow for activation of tumor-reactive T-lymphocytes and have been approved for treatment of a number of cancers and malignancies.

Mutations in CTLA-4 have previously been associated with a number of endocrine disorders – including type 2 diabetes (T2D), thyroid disorders (including Graves’ disease and hypothyroidism), and Addison’s disease.  Autoimmune endocrine disorders also occur in response to genetic mutations associated with CTLA-4. It is therefore not surprising that patients receiving CPIs are at risk for a variety of endocrine disorders.

Clinical Implications for Patients with Checkpoint Inhibitor-induced Endocrine Disorders

Although CPI-induced endocrine disorders are increasing, Dr. Herold and Dr. Vellanki are in agreement against the need to recommend routinely screening all patients receiving CPIs for diabetes. However, Dr. Herold said, “it may be worth looking further into patients with a history of T2D to determine if they possibly have type 1 diabetes that was misdiagnosed as type 2 diabetes.”  

In some cases, patients may have had pre-existing endocrine disorders prior to treatment with CPIs; in other cases, treatment with CPIs may cause endocrine disorders. For many patients, there is no pre-existing personal or family history of endocrine disorders.

They both agreed that there was little to be done, so far, to prevent the development of CPI-induced endocrine disorders. “Many patients in Dr. Herold’s study had normal baseline HbA1c levels,” Dr. Vellanki said.

Benefits of Check-Point Inhibition Outweigh the Slight Risk of Adverse Endocrine  Outcomes

“While conventional approaches to treatment work with patients who develop thyroid disorders from CPI therapies, and steroids may help prevent pituitary disorders, patients who develop CPI-induced diabetes need to be treated with insulin, along with the other conventional lifestyle approaches to diabetes education, diet, and exercise,” said Dr. Herold. When asked, he said that continuous glucose monitoring might be appropriate for some patients, although it is not yet clear how to identify who would best benefit.

Both Dr. Herold and Dr. Vellanki agreed strongly that the key take-away message from this (and supported by other similar studies) is to be more vigilant about recognizing symptoms of autoimmune disorders and DKA–even in the absence of diabetes. In addition, neither would discourage patients from using CPIs because of these possible risks as the benefits of CPIs far outweigh the unlikely risk of known adverse effects.

Primary Funding for this study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Continue Reading:
Addressing Thyroiditis Triggered by Cancer Immunotherapy
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