New CAR T-Cell Therapy for Multiple Myeloma Targets GPRC5D

Researchers have identified a potential new target for chimeric antigen receptor (CAR) T-cell therapy in patients with multiple myeloma: a protein called G protein–coupled receptor, class C group 5 member D-or GPRC5D.

Currently, CAR T-cell–based immunotherapy in patients with myeloma has targeted B-cell maturation antigen (BCMA), which is expressed on most malignant plasma cells.

“BCMA-targeted CAR T-cell therapy has been shown by our group and others to induce frequent, deep responses in relapsed/refractory multiple myeloma,” said Eric L. Smith, MD, PhD, a medical oncologist and director of clinical translation in the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York. “However, in many patients relapses still occur.”

Early research into GPRC5D showed that the protein was expressed in the hair follicle, and in the bone marrow of patients with myeloma.

In their study, published in Science Translational Medicine, Smith and colleagues wanted to confirm the expression of GPRC5D in the bone marrow of patients with myeloma, with a distribution that was similar to, but independent of, BCMA.

“Our report in STM identifies GPRC5D protein on the cell surface of myeloma cells in the majority of patients,” Smith told Cancer Network.

GPRC5D was absent from nearly all healthy tissues, according to the study. In addition, the percentage of CD138⁺ cells that expressed BCMA did not correlate with an expected percent of GPRC5D expression in any individual patient, the researchers wrote.

“We go on to develop a fully human, optimized CAR T-cell therapy targeting GPRC5D that efficiently eradicated multiple myeloma cells in mouse models, including in a model of BCMA antigen loss–mediated relapse,” Smith said.

In the experiments, the mice had no clinical signs of toxicity; however, the researchers noted that these results are limited “by the use of a surrogate species cross-reactive CAR binders.”

“It is not yet firmly established whether or how the degree of BCMA expression may affect the efficacy of BCMA-targeted CAR T-cell therapy, but it is possible that targeting a second antigen with an independent expression pattern, such as GPRC5D, may increase the frequency, depth, and/or duration of responses in patients harboring BCMA-low or BCMA-negative multiple myeloma plasma cell reservoirs,” the researchers wrote.

In the future, Smith and colleagues will be evaluating these results in a clinical trial at Memorial Sloan Kettering for patients with and without prior anti-BCMA–directed therapy.