Coming at you this morning is a steamy cup of morning report pearls from yesterday’s extravaganza with the ZSFG ICU team.
Thank you to Alan, Braden, Evan and Ty (our pulmonary/critical care consultant expert) for a riveting discussion of an older man who presented with altered mental status and was found to have DKA in setting of PD-1 inhibitor (Pembrolizumab) precipitated autoimmune diabetes.
Tell me (just a little) more about Pembrolizumab and these checkpoint inhibitors you say?!
- Monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block programmed death ligand 1 (PD-L1) from binding (see image below)
- PemBROlizumab has a BRO, Nivolumab which also targets PD-1 receptor, and both were approved in 2014 for advanced melanoma
- Mechanism involves T cell activation which attacks the tumors, but the immune response is nonspecific
- Lack of direct activity against malignant cells means that there is immune-related adverse events (irAE’s) which occur secondary to reduced tolerance to antigens previously recognized as self-antigens
- Common irAE’s: dermatologic, GI (colitis), hepatic, endocrine (thyroiditis, hypophysitis, DM, AI), and neurologic
In this particular case, the pt presented with DKA and significant hyperglycemia, not improving despite increasing doses of an insulin gtt (up to 800u/hr), making the team wonder if there was something else creating insulin resistance or binding/blocking the receptor. In this situation, the bro Pembrolizumab may be the clue…
Autoimmune Diabetes with PD-1 inhibitors
- Pembrolizumab has been implicated in precipitating type B insulin resistance with the production of autoantibodies to the surface insulin receptor (see Diabetes Journal article below)
- Type B insulin resistance is characterized diabetes refractory to massive doses of insulin (800u/hr for this patient), along with dramatic weight loss, hyperandrogenism, acanthosis nigricans
- Treatment of the autoimmune diabetes includes immunosuppression with rituximab, cyclophosphamide, corticosteroids and potentially plasmapheresis all aimed at controlling pathogenic autoantibody production (see first reference article)
- Recent literature (Cancer Immunology editorial below) describes the potential role for evaluation of HLA type that may predispose to developing autoimmune diabetes when initiating a patient on PD-1 inhibitors
- Malek R, Chong AY, Lupsa BC, et al. Treatment of Type B Insulin Resistance: A Novel Approach to Reduce Insulin Receptor Autoantibodies. The Journal of Clinical Endocrinology and Metabolism. 2010;95(8):3641-3647. doi:10.1210/jc.2010-0167; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913034/
- Spain, L., Larkin, J. & Martin-Liberal, J. Cancer Immunol Immunother (2016) 65: 769. doi:10.1007/s00262-016-1845-2