Research ArticleCancer Immunotherapy

GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells

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Science Translational Medicine  27 Mar 2019:
Vol. 11, Issue 485, eaau7746
DOI: 10.1126/scitranslmed.aau7746

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CARs to drive away multiple myeloma

Chimeric antigen receptor (CAR) T cells, a type of cell-based immunotherapy, have shown some promising results in multiple myeloma, a bone marrow cancer. These earlier CAR T cells targeted a protein called B cell maturation antigen, but some patients’ cancer cells expressed little to none of this antigen and were therefore resistant to the CAR T cells. Smith et al. identified another target antigen for multiple myeloma, called GPRC5D. The authors demonstrated that CAR T cells against GPRC5D are effective in mouse models, even those with tumors that are resistant to the earlier CARs, and they are safe in mice and primates.

Abstract

Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell–derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.

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