GPRC5D-Targeted CAR T-Cells Show Efficacy in Phase 1 R/R MM Trial

All 10 patients with relapsed/refractory multiple myeloma (R/R MM) in a phase 1 trial responded to treatment with an autologous chimeric antigen receptor (CAR) T-cell therapy targeting the receptor GPRC5D, according to results published in Lancet Haematology.¹

In the first-in-human phase 1 POLARIS study (NCT05016778), there was a 100% overall response rate to the therapy, OriCAR-017, including 6 out of 10 patients with a stringent complete response (sCR). Grade 3 and 4 hematologic toxicities were observed but were controllable.

“Data from our study showed that with extraordinary clinical efficacy, OriCAR-017 has been proved to be a novel, safe and effective therapy for patients with R/R MM, especially for those who experienced a relapse after receiving BCMA [B-cell maturation antigen]-targeted therapy,” He Huang, MD, PhD, chancellor and associate dean of Zhejiang University School of Medicine, said in a press release from Oricell Therapeutics.² “We are looking forward to continuously conducting follow-up clinical studies of OriCAR-017 in concert with Oricell.”

GPRC5D is an orphan G protein­–coupled receptor normally expressed in the hair follicle that is present in MM cells, showing the potential for targeting with CAR T cells.³ Its expression is independent of BCMA, making it a potential target in patients whose disease progressed after BCMA-targeted therapy.

The POLARIS study, performed at the First Affiliated Hospital of Zhejiang University School of Medicine in Hangzhou, China, enrolled patients with R/R MM who had received at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and chemotherapy. They were required to have 20% GPRC5D expression in bone marrow plasma cells or be GPRC5D-positive by immunohistochemistry.¹

Patients in the dose escalation portion received a single intravenous infusion of OriCAR-017 at 1 × 10⁶ CAR T cells per kg, 3 × 10⁶ CAR T cells per kg, or 6 × 10⁶ CAR T cells per kg. The primary end points were safety, maximum tolerated dose, and recommended phase 2 dose (RP2D).

Thirteen patients were recruited; 1 was excluded due to lack of GPRC5D expression and 2 more due to rapid progression after apheresis. The RP2D dose was determined to be 3 × 10⁶ CAR T cells per kg. One additional patient received this dose in the dose expansion phase, but recruitment for this part of the trial was discontinued early due to the COVID-19 pandemic. Five out of 10 treated patients had received prior BCMA-targeted CAR T-cell therapy.

At a median follow-up of 238 days (interquartile range, 182–307), 6 patients had an sCR, and the other 4 had a very good partial response (VGPR). All 10 patients achieved minimal residual disease negativity status at the 10-5 level.² Of the 5 patients who had received prior BCMA-targeted CAR T-cell therapy, there were 2 sCRs and 3 VGPRs.

In terms of adverse events, cytokine release syndrome was observed in all patients but only 1 patient had grade 2 toxicity; all others had grade 1. No dose-limiting toxicities, serious adverse events, incidences of neurotoxicity, or treatment-related deaths were reported. Grade 3 and 4 adverse events included neutropenia in 10 patients, leukopenia and thrombocytopenia in 9 patients each, and anemia in 7 patients.

OriCAR-017 received Orphan Drug Designation in the United States from the FDA in October 2022.² Based on the results of this trial, Oricell Therapeutics intends to pursue clinical studies in China and the United States to evaluate the efficacy of this therapy on a larger scale.

"OriCAR-017 has demonstrated 100% ORR and controllable safety in the POLARIS study, providing a solid foundation for Oricell's subsequent registration of clinical studies," Helen Yang, chairman and CEO of Oricell, said in a statement. "The firm is in the process of submitting an application in the [United States] and China for the registration of clinical studies of OriCAR-017 while advancing the therapy to critical phases of clinical research as soon as possible."

_References:

_{1. Zhang M, Wei G, Zhou L, et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol. 2023;10(2):e107-e116. doi:10.1016/S2352-3026(22)00372-6}

_{2. Oricell Publishes Data from POLARIS Clinical Study Evaluating OriCAR-017 in the Treatment of RRMM in The Lancet Haematology. January 30, 2023. Accessed February 2, 2023. https://prn.to/3X0VO3D}

_{3. Smith EL, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746. doi:10.1126/scitranslmed.aau7746}