Activating Antibodies to Calcium-Sensing Receptor In Immunotherapy-Induced Hypoparathyroidism

CONTEXT: Immune checkpoint inhibitors (ICIs), as anti-programmed cell death protein-1 (PD-1), anti-programmed cell death protein-ligand 1 (PD-L1), and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. OBJECTIVES: The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. METHODS: Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, Ig subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. RESULTS: The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalised with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a nine-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. CONCLUSION: The finding confirms that ICIs therapy can trigger, amongst other endocrinopathies, hypoparathyroidism which can be caused by pathogenic autoantibodies.