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Research Article
CANCER IMMUNOTHERAPY

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

Eric L. Smith https://orcid.org/0000-0002-0296-7587, Kim Harrington, Mette Staehr https://orcid.org/0000-0001-8680-4373, Reed Masakayan https://orcid.org/0000-0003-3591-8869, Jon Jones https://orcid.org/0000-0003-3870-3337, Thomas J. Long, Khong Y. Ng https://orcid.org/0000-0003-4373-850X, Majid Ghoddusi https://orcid.org/0000-0001-7552-2418, Terence J. Purdon, Xiuyan Wang, Trevor Do, Minh Thu Pham, Jessica M. Brown https://orcid.org/0000-0001-9031-9987, Carlos Fernandez De Larrea, Eric Olson, Elizabeth Peguero https://orcid.org/0000-0003-2387-3595, Pei Wang, Hong Liu, Yiyang Xu, Sarah C. Garrett-Thomson https://orcid.org/0000-0002-3073-1571, Steven C. Almo, Hans-Guido Wendel https://orcid.org/0000-0001-7166-4670, Isabelle Riviere, Cheng Liu, Blythe Sather https://orcid.org/0000-0001-6582-0243, and Renier J. Brentjens https://orcid.org/0000-0002-3364-5388 [email protected]
Science Translational Medicine • 27 Mar 2019 • Vol 11, Issue 485 • 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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Supplementary Material

Summary

Materials and Methods
Fig. S1. SDC1 (CD138) and GPRC5D mRNA expression.
Fig. S2. Correlation of higher GPRC5D expression by MM cells with shorter progression-free survival.
Fig. S3. GPRC5D protein expression on control cells.
Fig. S4. Representative flow cytometric analyses of antigen-independent and antigen-specific activation using the Jurkat Nur77-RFP reporter line.
Fig. S5. GPRC5D(109) CAR T cell–mediated cytotoxicity of MM cell lines with varying GPRC5D expression.
Fig. S6. Lysis of primary bone marrow aspirate MM cells by GPRC5D-targeted CAR T cells.
Fig. S7. Cytokine secretion by GPRC5D-targeted CAR T cells upon coculture with GPRC5D-expressing cells.
Fig. S8. Requirement of GPRC5D expression for activation through GPRC5D(109) CAR.
Fig. S9. Comparable surface expression of different CAR vectors on primary T cells.
Fig. S10. In vivo expansion and antitumor activity of GPRC5D-targeted CAR T cells in an RPMI-8226 MM xenograft model.
Fig. S11. Eradication of OPM2BCMA-KO MM cells by GPRC5D-targeted CAR T cells.
Fig. S12. Minimal cytokine release by GPRC5D-targeted CAR T cells upon coculture with primary human cell types isolated from normal tissues.
Fig. S13. Screening for murine and cynomolgus cross-reactive scFv clones.
Fig. S14. Schematic of the NHP study protocol.
Fig. S15. Viability and functionality of cynomolgus GPRC5D(108) CAR T cells.
Table S1. GPRC5D expression in normal tissue.
Table S2. Single chromogenic immunostaining conditions.
Table S3. Antibodies and reagents for IHC and RNA-ISH.
Table S4. Multiplex immunostaining conditions.
Data file S1. Original data.

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Science Translational Medicine
Volume 11 | Issue 485
March 2019

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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 19 July 2018
Accepted: 8 March 2019

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Acknowledgments

We would like to thank S. Yoo, P. Carlson, T. Cox, J. Freeth, C. Hauskins, C. Herr, Y. Ho, C. de Imus, A. Lickteig, S. Morkowski, M. Myers, and L. Torrey for technical assistance; J. Moore (MSKCC Editorial and Grant Services) for editorial support; S. Weil (MSKCC Medical Graphics) for assistance with presentation of data; and M. Blake, C. Davis, C. Hordo, R. Guzman, B. Moyer, R. Ponce, R. Salmon, S. Moulis, J. Schwartz, S. Sequeira, E. Levine, A. Jungbluth, M. Roshal, Q. Gao, A. Dogan, S. Mailankody, S. Monette, S. Giralt, and O. Landgren for scientific and strategic discussions. Funding: E.L.S. is a Special Fellow of The Leukemia & Lymphoma Society and an American Society of Hematology Scholar. Additional support was provided by an MSKCC Technology Development Grant, the Multiple Myeloma Research Foundation, the Lymphoma Research Foundation, and the Society of Immunotherapy for Cancer. S.C.A. reports support from the NIH (R01 HG008325 and R01 CA198095) and the Albert Einstein Cancer Center (P30 CA013330). R.J.B. reports support from the NIH (R01 CA138738-05, P01 CA059350, and PO1 CA190174-01), the annual Terry Fox Run for Cancer Research organized by the Canada Club of New York, Kate’s Team, the Carson Family Charitable Trust, the William Lawrence and Blanche Hughes Foundation, the Emerald Foundation, and the Experimental Therapeutics Center of MSKCC. All MSK investigators acknowledge the MSKCC Core Facilities Grants (P30 CA008748 and U54 OD020355-01). Author contributions: E.L.S. and R.J.B. conceptualized the study. E.L.S., B.S., C.L., K.H., M.S., R.M., J.J., T.J.L., M.G., S.C.A., Y.X., and H.L. chose and developed the methodology. E.L.S., B.S., K.H., M.S., R.M., J.J., T.J.L., K.Y.N., M.G., T.J.P., T.D., M.T.P., J.M.B., C.F.D.L., E.O., E.P., S.C.G.-T., H.L., and Y.X. conducted experiments, validated assays, and analyzed data. I.R., X.W., S.C.A., and C.L. provided technical resources. E.L.S. drafted the paper. B.S., K.H., T.J.L., J.J., M.G., S.C.A., P.W., X.W., and R.J.B. reviewed and edited the paper. E.L.S., B.S., K.H., and P.W. coordinated and managed the project. E.L.S., B.S., K.H., H.-G.W., I.R., S.C.A., C.L., and R.J.B. supervised the study. E.L.S., H.-G.W., S.C.A., and R.J.B. provided funding. Competing interests: E.L.S., R.J.B., and C.L. have licensed intellectual property to and collect royalties from Juno Therapeutics, A Celgene Company. E.L.S., R.J.B., and I.R. receive research funding from Juno Therapeutics, A Celgene Company. E.L.S. and R.J.B. are consultants for Juno Therapeutics, A Celgene Company. E.L.S. is a consultant for Fate Therapeutics. C.F.D.L. has received research funding and is a consultant for Celgene, Janssen, Takeda, and Amgen. P.W., H.L., Y.X., and C.L. are employed by and hold equity in Eureka Therapeutics. I.R. receives research funding from Fate Therapeutics. K.H., J.J., T.J.L., M.T.P., and E.O. are employed by and hold equity in Juno Therapeutics, A Celgene Company. B.S. and M.G. were employed at Juno Therapeutics, A Celgene Company during their involvement in all work within this manuscript. B.S. is currently an employee and equity shareholder of Lyell Immunopharma. M.G. is currently an employee of Poseida Therapeutics and is an equity shareholder of Celgene and Poseida Therapeutics. R.M. and E.P. were employed by MSKCC during their involvement in all work within this manuscript. R.M. is currently employed by AgenTus Therapeutics Inc. E.P. is currently employed by Regeneron. E.L.S., C.L., and R.J.B. acknowledge filed patent application WO2016/090312 “Chimeric antigen receptors targeting g-protein coupled receptor and uses thereof” related to the work disclosed in this paper. All other authors declare that they have no competing interests. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. OPM2, RPMI-8226, and MM1.S human myeloma cell lines expressing ffLuc and guide RNAs for CRISPR KO of GPRC5D and BCMA are available from R.J.B. under a material transfer agreement with MSKCC.

Authors

Affiliations

Eric L. Smith https://orcid.org/0000-0002-0296-7587
Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Kim Harrington
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Mette Staehr https://orcid.org/0000-0001-8680-4373
Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Reed Masakayan https://orcid.org/0000-0003-3591-8869
Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Jon Jones https://orcid.org/0000-0003-3870-3337
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Thomas J. Long
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Khong Y. Ng https://orcid.org/0000-0003-4373-850X
Sloan Kettering Institute, New York, NY 10065, USA.
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Majid Ghoddusi https://orcid.org/0000-0001-7552-2418
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Terence J. Purdon
Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Xiuyan Wang
Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Trevor Do
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Minh Thu Pham
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Jessica M. Brown https://orcid.org/0000-0001-9031-9987
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Carlos Fernandez De Larrea
Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain.
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Eric Olson
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Elizabeth Peguero https://orcid.org/0000-0003-2387-3595
Sloan Kettering Institute, New York, NY 10065, USA.
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Pei Wang
Eureka Therapeutics, Emeryville, CA 94608, USA.
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Hong Liu
Eureka Therapeutics, Emeryville, CA 94608, USA.
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Yiyang Xu
Eureka Therapeutics, Emeryville, CA 94608, USA.
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Sarah C. Garrett-Thomson https://orcid.org/0000-0002-3073-1571
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Steven C. Almo
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Hans-Guido Wendel https://orcid.org/0000-0001-7166-4670
Sloan Kettering Institute, New York, NY 10065, USA.
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Isabelle Riviere
Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Cheng Liu
Eureka Therapeutics, Emeryville, CA 94608, USA.
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Blythe Sather https://orcid.org/0000-0001-6582-0243
Juno Therapeutics, A Celgene Company, Seattle, WA 98109, USA.
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Renier J. Brentjens* https://orcid.org/0000-0002-3364-5388 [email protected]
Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Funding Information

National Cancer Institute: U54 OD020355-01
National Cancer Institute: PO1 CA190174-01
National Cancer Institute: R01 CA138738-05

Notes

*Corresponding author. Email: [email protected]

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