Abstract
The orphan G protein-coupled receptor GPRC5D is a target for immunotherapy in multiple myeloma.
Major finding: The orphan G protein–coupled receptor GPRC5D is a target for immunotherapy in multiple myeloma.
Clinical relevance: In a mouse model of multiple myeloma, GPRC5D-targeted CAR T-cell therapy is rapid, specific, and safe.
Impact: GPRC5D-specific immunotherapy may be effective against both primary and relapsed multiple myeloma.
Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown some efficacy in patients with multiple myeloma. However, BCMA expression is heterogeneous and relapse associated with BCMA downregulation remains a significant challenge, underscoring the importance of identifying additional therapeutic targets. Smith and colleagues evaluated the orphan G protein-coupled receptor, class C group 5 member D (GPRC5D) as a potential target for CAR T-cell therapy in multiple myeloma. Normally restricted to the hair follicle, GPRC5D protein was found to be expressed on the surface of greater than 50% of CD138+ multiple myeloma cells from 65% of primary bone marrow samples, independent of BCMA expression. A single-chain variable fragments phage display library screen identified 32 distinct clones reactive against GPRC5D, seven of which were engineered into CARs of various structural formats, each containing a CD28 transmembrane domain and 4-1BB and CD3ζ signaling domains. CARs containing a long spacer exhibited high GPRC5D-specific signaling, and a CAR that induced minimal antigen-independent signaling was identified. Human T cells expressing GPRC5D-specific CARs induced cytokine secretion and cytotoxicity against human multiple myeloma cell lines and eliminated primary multiple myeloma cells from bone marrow aspirates. GPRC5D CAR T cells interacted with and were specifically activated by GPRC5D on the surface of target cells. In vivo, GPRC5D-specific CAR T cells injected into a human multiple myeloma xenograft model characterized by bone marrow–predominant disease rapidly localized to the tumor, eradicated multiple myeloma cells, and increased survival, with comparable efficacy to BCMA-targeted CAR T cells. Moreover, GPRC5D-specific CAR T-cell therapy successfully rescued mice from antigen escape–mediated tumor progression following BCMA-targeted immunotherapy. In addition, GPRC5D-specific CAR T cells did not exhibit any overt on-target/off-tumor toxicity in murine and cynomolgus models. These findings identify GPRC5D as an attractive target for immunotherapy in patients with multiple myeloma, regardless of prior BCMA-targeted therapy.
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