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


Authors: Smith, E. L.; Harrington, K.; Staehr, M.; Masakayan, R.; Jones, J.; Long, T. J.; Ng, K. Y.; Ghoddusi, M.; Purdon, T. J.; Wang, X.; Do, T.; Pham, M. T.; Brown, J. M.; De Larrea, C. F.; Olson, E.; Peguero, E.; Wang, P.; Liu, H.; Xu, Y.; Garrett-Thomson, S. C.; Almo, S. C.; Wendel, H. G.; Riviere, I.; Liu, C.; Sather, B.; Brentjens, R. J.
Article Title: GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells
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. © 2019 American Association for the Advancement of Science. All Rights Reserved.
Keywords: signal transduction; cancer survival; controlled study; protein expression; unclassified drug; human cell; nonhuman; protein analysis; animal cell; mouse; animal tissue; multiple myeloma; protein targeting; animal experiment; animal model; in vivo study; cytotoxicity; immunofluorescence; b lymphocyte; messenger rna; bone marrow biopsy; quantitative analysis; chimeric antigen receptor; cytokine release; alopecia; g protein coupled receptor; single chain fragment variable antibody; nuclear receptor nur77; long term survival; human; priority journal; article; multiple myeloma cell line; b cell maturation antigen; chimeric antigen receptor t-cell immunotherapy; g protein coupled receptor class c group 5 member d
Journal Title: Science Translational Medicine
Volume: 11
Issue: 485
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2019-03-27
Start Page: eaau7746
Language: English
DOI: 10.1126/scitranslmed.aau7746
PUBMED: 30918115
PROVIDER: scopus
DOI/URL:
Notes: Source: Scopus
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