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 immunerelated 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.