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Phase I Study Shows Preliminary Efficacy of GPRC5D-Directed CAR T-Cell Therapy in R/R MM

April 4, 2023

May 2023

Brandon May

Brandon May is a medical journalist based in Detroit.

An investigational chimeric antigen receptor (CAR) T-cell therapy targeting G protein-coupled receptor class C group 5 member D (GPRC5D) showed preliminary efficacy and favorable safety in patients with relapsed or refractory (R/R) multiple myeloma (MM), according to findings from the phase I POLARIS trial.1

OriCAR-017 is an investigational, autologous CAR T-cell therapy targeting GPRC5D, an orphan G protein-coupled receptor that is present in MM cells. The expression of GPRC5D is limited to plasma cells and hair follicles and is independent of B-cell maturation antigen (BCMA),2 suggesting GPRC5D could be a therapeutic target for patients with R/R MM who have experienced progression after BCMA-targeted treatment.

The first-in-human POLARIS trial, conducted by Mingming Zhang, PhD, of Zhejiang University in China, and colleagues, investigated the preliminary safety and efficacy of OriCAR-017. The study enrolled 13 adults with R/R MM who had an Eastern Cooperative Oncology Group performance status of 0 to 2. Study results were published in Lancet Haematology.

Patients in the study had received at least three prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and chemotherapy. For study entry, patients were also required to have 20% GPRC5D expression in bone marrow plasma cells or GPRC5D-positivity according to immunohistochemistry.

For the dose-escalation phase, patients were assigned to receive a single dose of intravenous 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. In the expansion phase, patients received a recommended phase II dose.

The study’s primary endpoints were safety, the maximum tolerated dose, and the recommended phase II dose. All patients who received OriCAR-017 were included in the safety and activity analyses.

Thirteen patients were recruited, and the manufacture of GPRC5D CAR T cells was successful in all patients. The investigators excluded one patient because of GPRC5D negativity. Additionally, two patients were suspended due to rapid disease progression. The remaining 10 patients received infusions. The dose-escalation phase included nine patients, with three patients each assigned to the three dose level groups. The dose-expansion phase included one patient who received a single dose level.

Half of all patients were women, and all patients were Chinese. Additionally, 50% of patients had previously received BCMA-targeted CAR T-cell therapy. The median follow-up period was 238 days.

No serious adverse events (AEs) or treatment-related deaths were reported. The most frequently reported grade 3 or worse AEs were hematologic in nature, including neutropenia (100%), thrombocytopenia (90%), leukopenia (90%), and anemia (70%). Grade 1 cytokine release syndrome (CRS) occurred in 90% of patients, while grade 2 CRS occurred in 10% of patients. There were no reports of neurologic toxicities during treatment.

Given that there were no observed dose-limiting toxic effects, the POLARIS investigators did not identify a maximum tolerated dose for the GPRC5D-targted CAR T cells. Safety and preliminary activity informed the recommended phase II dose of 3×106 CAR T cells per kg, which was administered to an additional patient during the dose-expansion phase.

All treated patients responded, with 60% experiencing a stringent complete response and 40% experiencing a very good partial response. Two patients discontinued the study because of disease progression, including one GPRC5D-positive patient in the 3×106 CAR T cells per kg dose group and one GPRC5D-negative patient in the 1×106 CAR T cells per kg dose group.

Limitations of the study included the small patient population, the lack of a placebo or control group, and the inclusion of only patients from China, which may limit the generalizability of the results.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

  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.
  2. Smith EL, Harrington K, Masakayan R, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485).

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