GPRC5D-Targeted CAR T Cells for Myeloma

BACKGROUND B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150x10(6) CAR T cells. At the 450x10(6) CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25x10(6) to 150x10(6) cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25x10(6) to 150x10(6) cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25x10(6) to 150x10(6) cells. CONCLUSIONS The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma.

Automated summary

The study demonstrates that GPRC5D is an active immunotherapeutic target in multiple myeloma, and GPRC5D-targeted CAR T-cell therapy shows promising efficacy in heavily pretreated patients, including those who relapsed after BCMA CAR T-cell therapy.