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Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care

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Published on: February 16, 2015

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.).

The New England Journal of Medicine

|September 28, 2022

Summary

G protein-coupled receptor, class C, group 5, member D (GPRC5D) targeted CAR T-cell therapy shows promise in multiple myeloma patients, including those who relapsed after BCMA therapy. This GPRC5D CAR T-cell therapy is an active target for multiple myeloma treatment.

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Area of Science:

Oncology
Immunotherapy
Cellular Therapy

Background:

B-cell maturation antigen (BCMA)-directed CAR T-cell therapies show efficacy but are limited by relapses in advanced multiple myeloma.
G protein-coupled receptor, class C, group 5, member D (GPRC5D) is identified as a novel immunotherapeutic target for multiple myeloma.
Preclinical data support the efficacy of GPRC5D-targeted CAR T-cells, including in models of BCMA antigen escape.

Purpose of the Study:

To evaluate the safety and efficacy of a GPRC5D-targeted CAR T-cell therapy (MCARH109) in a phase 1 dose-escalation study.
To determine the maximum tolerated dose (MTD) of MCARH109 in patients with heavily pretreated multiple myeloma.
To assess response rates in patients receiving MCARH109, including those with prior BCMA-targeted therapy.

Main Methods:

A phase 1 dose-escalation study involving 17 patients with heavily pretreated multiple myeloma.
Administration of MCARH109 at four dose levels.
Patients included those who had relapsed after prior BCMA CAR T-cell therapy.

Main Results:

The maximum tolerated dose (MTD) was established at 150×10^6 CAR T cells.
No grade 3 or higher cytokine release syndrome, ICANS, or cerebellar disorder occurred at doses up to 150×10^6 cells.
Overall response rate was 71% in the cohort, and 58% in patients receiving 25×10^6 to 150×10^6 cells. Responses were observed in 7 of 10 patients with prior BCMA therapy.

Conclusions:

GPRC5D-targeted CAR T-cell therapy (MCARH109) demonstrates that GPRC5D is an active immunotherapeutic target in multiple myeloma.
MCARH109 shows a favorable safety profile at doses up to 150×10^6 cells, with promising response rates in heavily pretreated patients.
The study confirms the potential of GPRC5D as a therapeutic target for patients with multiple myeloma, including those resistant to BCMA-targeted therapies.