Endocrine diseases ‘emerging epidemic’ after immune checkpoint inhibitor therapies
LOS ANGELES — Recently approved immune checkpoint inhibitor therapies are now increasingly used for a variety of cancers and other conditions, yet clinicians are only beginning to confront a range of endocrinopathies triggered by such treatments, including thyroid disease, pituitary disorders and insulin-dependent diabetes, according to a speaker here.
“This is an emerging epidemic of endocrine diseases that we will all be seeing,” Kevan Herold, MD, PhD, professor of immunobiology and medicine at Yale University, said during a plenary presentation at the AACE Annual Scientific and Clinical Congress. “At the end of the day, these endocrinopathies [after immune checkpoint inhibitor therapy] may be the most common form of endocrinopathies that we will ultimately see.”
Endocrine adverse events, such as hypopituitarism, hyperthyroidism, hypothyroidism and insulin-dependent diabetes, are common with the use of immune checkpoint inhibitors, such as CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors, and their frequency only increases with combination therapy, Herold said. Research suggests endocrine conditions are typically associated with specific therapies, Herold said. Hypophysitis, for example, is more common with the use of anti-CTLA-4 therapy, whereas thyroid disease and diabetes are seen more often with anti-PD-1 treatment; yet endocrine diseases are not exclusive to one treatment vs. another, he said.
The anti-tumor mechanisms of action of immune checkpoint inhibitors involve the relief of negative T cell costimulatory signals resulting from so-called T cell “exhaustion,” Herold said, which renders T cells unable to kill tumor cells. The monoclonal antibodies then block T cell exhaustion, enabling the tumor-reactive T cells to kill the tumor cells.
“The problem for us is that these same mechanisms are potentially going to lead to autoimmune diseases, particularly in the pituitary, the thyroid, the adrenal and the beta cells,” Herold said. “But by understanding the mechanisms that are involved in causing the anti-tumor response, we can also gain a lot of insight into what might be going on with these autoimmune diseases.”
Mechanisms behind endocrin opathies
Several possible mechanisms have been proposed to explain the development of endocrine conditions with checkpoint inhibitor therapy, Herold said, including T cell- or cytokine- mediated processes, humoral immunity, tissue-dependent processes and a possible role for the gut microbiome. Additionally, studies suggest that checkpoint inhibitory ligands may be expressed on endocrine cells, he said. In the pituitary, for example, the expression of CTLA-4 may lead to complement activation and “cell killing” when ipilimumab is given, Herold said. On beta cells, PD-L1 expression appears to identify cells that are likely to be killed by cellular events, he said.
Features of patients who are most likely to develop endocrinopathies are beginning to emerge, Herold said. As an example, he noted that the HLA-DR4 serotype appears to identify patients who are more likely to develop autoimmune diabetes. Additionally, intriguing data suggest those who develop endocrine adverse events have improved anti-tumor responses when compared with those who do not develop endocrine conditions; however, more data are needed to confirm this initial impression, Herold said.
Herold outlined several common endocrinopathies that can develop after immune checkpoint inhibitor therapy:
Hypophysitis — Between 10% and 17% of patients prescribed ipilimumab or combination therapy will develop inflammation of the pituitary gland within 8 to 9 weeks after treatment initiation or after the third dose, Herald said. Visual changes are uncommon; patients may present with fatigue or mass effects, or there may also be hormone defects, such as hypoadrenalism. Diabetes insipidus has been reported uncommonly with the condition, he said. Steroid treatment as replacement is commonly needed, and high-dose steroids may be used to manage mass effects, Herold said. However, agents that can prevent the occurrence of adverse events without interfering with the anti-tumor effects of the checkpoint inhibitors are not available, Herold said. “This, of course, is the holy grail of where we want to go,” Herold said. “We want to find something that will block the endocrine adverse events without blocking the anti-tumor effects.”
Thyroid disease — One of the most common checkpoint inhibitor-induced conditions is thyroid disease, which most often occurs with anti-PD1 treatment or a combination of anti-PD1 with anti-CTLA-4 treatment, Herold said. Thyroid disease presents in a variety of ways, although most often as hypothyroidism (subclinical or overt) or as transient thyrotoxicosis that often proceeds to hypothyroidism. Most patients are asymptomatic, though symptoms can include fatigue, weakness, palpitations or mood changes. True Graves’ disease, Herold added, is rare. “It has been suggested that positive thyroid antibodies prior to checkpoint inhibitor treatment may be a risk factor for development of thyroid disease,” Herold said. He recommended that TSH and T4 levels be checked before every treatment infusion or at least monthly. In severe cases, consider withholding the checkpoint inhibitor until the thyroid condition is appropriately treated, he said.
Insulin-dependent diabetes — Case reports are beginning to reveal that some patients treated with checkpoint inhibitors, typically anti-PD-1 or anti-PD-L1 therapies, develop new-onset autoimmune diabetes or a “dramatic increase” in insulin requirements for patients with type 2 diabetes, Herold said. In these cases, which frequently present as diabetic ketoacidosis, observed patients have rapidly progressed to having undetectable levels of C-peptide, and it does not appear that steroids will prevent the complete loss of beta cell function, he said. Recovery, he said, is rare.
“For the patients, this is a big deal,” Herold said. “They are insulin-dependent, for one, and you are talking about people who are in their 50s, 60s and 70s. The control of their diabetes is at least as difficult as it is for children with new-onset type 1 diabetes.” Herold said emerging data suggest that the number of people affected by new-onset or worsening diabetes due to checkpoint inhibitor therapy is likely much larger than previously thought. Researchers, in turn, are working to determine predictors of insulin-dependent diabetes to better manage outcomes. – by Regina Schaffer
Herold KC. Endocrine effects of checkpoint inhibitor therapy. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.
Disclosure: Endocrine Today was unable to determine relevant disclosures at the time of publication.