Parathyroid hormone related protein (PTHrP)-mediated hypercalcemia in malignancy associated with anti-PD-1 immune checkpoint inhibitor treatment and related inflammatory reactions

Over the last decade, the breakthrough of immune checkpoint inhibitors has revolutionized cancer therapeutics, an enterprise not devoid of a novel constellation of unique immune-related adverse events. In this article, we present the first two patients, one with metastatic urothelial bladder cancer and another one with inoperable non-small squamous cell lung carcinoma, with immune-related parathyroid hormone related protein (PTHrP)mediated hypercalcemia concurrent with immune-related pneumonitis following administration of anti-PD-1 monoclonal antibody nivolumab. The second patient present immune-related colitis as well. In both patients the hypercalcemia developed when cancer was in remission, rendering unlikely the diagnosis of humoral hypercalcemia of malignancy. The time of onset of PTHrP-mediated hypercalcemia-11 weeks and 15 weeks after initiation of nivolumab for the first and second patient respectively-insinuated the immune-related origin of PTHrP. The concurrent immune-related pneumonitis raised the question of whether the immune-related inflammatory milieu in the context of pneumonitis could be the source of the immune-related PTHrP. In conclusion, increased awareness of nivolumab-related hypercalcemia -an extremely rare immune-related adverse event-could enable the identification of immune-related elevation of PTHrP. Moreover, our cases provide the rationale for further research in pursuit of not only the source of immune-related PTHrP expression, but also of a causative link connecting the inflammatory milieu of immune-related pneumonitis and/or immune-related colitis with PTHrP-mediated hypercalcemia. Finally, the correlation of immune-related adverse events observed herein with response to nivolumab is in line with previous reports, necessitating further consolidation.