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

Eric L. Smith, Kim Harrington, Mette Staehr, Reed Masakayan, Jon Jones, Thomas J. Long, Khong Y. Ng, Majid Ghoddusi, Terence J. Purdon, Xiuyan Wang, Trevor Do, Minh Thu Pham, Jessica M. Brown, Carlos Fernandez De Larrea, Eric Olson, Elizabeth Peguero, Pei Wang, Hong Liu, Yiyang Xu, Sarah C. Garrett-ThomsonSteven C. Almo, Hans Guido Wendel, Isabelle Riviere, Cheng Liu, Blythe Sather, Renier J. Brentjens

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Article numbereaau7746
JournalScience translational medicine
Volume11
Issue number485
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Medicine(all)

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    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., ... Brentjens, R. J. (2019). GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Science translational medicine, 11(485), [eaau7746]. https://doi.org/10.1126/scitranslmed.aau7746