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GPRC5D-Targeted CAR T Cells for Myeloma
Sham Mailankody1, Sean M Devlin1, Jonathan Landa1
1From the Myeloma Service (S.M., U.A.S., N.K., A.L., C.R.T., M.H., H.H., O.L., S.Z.U.), the Cellular Therapy Service (S.M., K.N., L.F., B.C., T.F., G.L.S., A.L., S.A.G., J.H.P., S.Z.U.), the Adult Bone Marrow Transplantation Service (G.L.S., S.A.G.), and the Leukemia Service (J.H.P.), Department of Medicine, the Departments of Epidemiology and Biostatistics (S.M.D.), Radiology (J.L.), and Pathology and Laboratory Medicine (R.A., M.R., F.S., A.D.), the Cell Therapy and Cell Engineering Facility (X.W., D.S., B.S., V.P.B., I.R.), the Center for Cell Engineering and the Molecular Pharmacology Program (X.W., I.R.), and the Departments of Pediatrics (K.H., D.P.M.), Anesthesiology and Critical Care Medicine (E.M., S.Z.U.), and Neurology (J.A.W., B.D.S.), Memorial Sloan Kettering Cancer Center, and the Department of Medicine, Weill Cornell Medical College (S.M., G.L.S., U.A.S., N.K., A.L., C.R.T., M.H., H.H., S.A.G., J.H.P., S.Z.U.), New York, and the Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo (C.D., T.J.P., R.J.B.) - all in New York; the Department of Medical Oncology, Dana-Farber Cancer Center, Boston (E.J.C., D.R., E.L.S.); and the Myeloma Division, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami (O.L.).
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 150×106 CAR T cells. At the 450×106 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 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 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 25×106 to 150×106 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. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).
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