Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors

Abstract

Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti-PD-1 or anti-PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti-PD-1 or -PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.

Figure 1

Immunologic actions of CPIs. Top: Blockade of negative costimulatory signals (checkpoints) leads to activation of T cells and endows their ability to kill tumor cells. Bottom: The most widely used strategies block CTLA-4, which is expressed on activated T cells and binds to B7.1 (CD80) and B7.2 (CD86), which is expressed on antigen-presenting cells (e.g., dendritic cells). In addition, other mAbs have targeted the interaction between PD-1, expressed on T cells, and PD-L1, expressed on tumor and other cells.

Figure 2

Timing of hyperglycemia after CPI treatment. The symbols indicate the weeks between the initial treatment with CPI and the time of diagnosis of insulin-dependent diabetes. Black symbols indicate exposure to a single CPI indicated on the y-axis. Gray symbols indicate whether additional CPIs were used. The numbers in the circles refer to the treatment cycles that were administered.