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Clinical Trial
. 2022 Sep 29;387(13):1196-1206.
doi: 10.1056/NEJMoa2209900.

GPRC5D-Targeted CAR T Cells for Myeloma

Sham Mailankody  1 , Sean M Devlin  1 , Jonathan Landa  1 , Karthik Nath  1 , Claudia Diamonte  1 , Elizabeth J Carstens  1 , Douglas Russo  1 , Romany Auclair  1 , Lisa Fitzgerald  1 , Briana Cadzin  1 , Xiuyan Wang  1 , Devanjan Sikder  1 , Brigitte Senechal  1 , Vladimir P Bermudez  1 , Terence J Purdon  1 , Kinga Hosszu  1 , Devin P McAvoy  1 , Tasmin Farzana  1 , Elena Mead  1 , Jessica A Wilcox  1 , Bianca D Santomasso  1 , Gunjan L Shah  1 , Urvi A Shah  1 , Neha Korde  1 , Alexander Lesokhin  1 , Carlyn R Tan  1 , Malin Hultcrantz  1 , Hani Hassoun  1 , Mikhail Roshal  1 , Filiz Sen  1 , Ahmet Dogan  1 , Ola Landgren  1 , Sergio A Giralt  1 , Jae H Park  1 , Saad Z Usmani  1 , Isabelle Rivière  1 , Renier J Brentjens  1 , Eric L Smith  1
Affiliations
Clinical Trial

GPRC5D-Targeted CAR T Cells for Myeloma

Sham Mailankody et al. N Engl J Med. .

Abstract

Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model.

Methods: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy.

Results: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells.

Conclusions: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).

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Figures

Figure 1.
Figure 1.. Clinical Responses to GPRC5D-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy.
Panel A shows a swimmer’s plot of clinical responses over time. The star indicates a patient who discontinued the study without progression of disease. Panel B shows positron-emission tomographic (PET) scans at baseline and after treatment in Patient 1, who received the dose of 25×106 CAR T cells. Panel C shows MCARH109 expansion over time among all the patients. GPRC5D denotes G protein–coupled receptor, class C, group 5, member D.
Figure 2.
Figure 2.. Loss of GPRC5D on Immunohistochemical Analysis at Relapse after MCARH109 Infusion.
GPRC5D and CD138 immunohistochemical analysis of plasmacytoma tissue samples from Patient 15 at baseline and at relapse after MCARH109 infusion (dose level, 150×106 CAR T cells) shows loss of GPRC5D expression at the time of relapse. The patient had a best response of stringent complete response.
See this image and copyright information in PMC

Comment in

  • GPRC5D-CAR T cells active in MM.
    Killock D. Killock D. Nat Rev Clin Oncol. 2022 Dec;19(12):747. doi: 10.1038/s41571-022-00701-6. Nat Rev Clin Oncol. 2022. PMID: 36253450 No abstract available.
  • GPRC5D-Targeted CAR T Cells for Myeloma.
    Quintás-Cardama A. Quintás-Cardama A. N Engl J Med. 2022 Dec 15;387(24):2295-2296. doi: 10.1056/NEJMc2213985. N Engl J Med. 2022. PMID: 36516097 No abstract available.
  • GPRC5D-Targeted CAR T Cells for Myeloma. Reply.
    Mailankody S, Brentjens RJ, Smith EL. Mailankody S, et al. N Engl J Med. 2022 Dec 15;387(24):2296. doi: 10.1056/NEJMc2213985. N Engl J Med. 2022. PMID: 36516098 No abstract available.

References

    1. Shah UA, Mailankody S. Emerging immunotherapies in multiple myeloma. BMJ 2020; 370:m 3176. - PubMed
    1. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021; 384: 705–16. - PubMed
    1. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 2021; 398: 314–24. - PubMed
    1. Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol 2022. June 4 (Epub ahead of print). - PMC - PubMed
    1. Chong EA, Ruella M, Schuster SJ. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N Engl J Med 2021; 384: 673–4. - PubMed

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