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Cited by 166CAR-T cell therapy researchMultiple Myeloma Research and TreatmentsImmunotherapy and Immune Responses

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

Zhang, Mingming, Wei, Guoqing, Zhou, Linghui, Zhou, Jincai, Chen, Siye, Zhang, Wei, Wang, Dongrui, Luo, Xueping +10 more·2023·The Lancet Haematology
DOI 10.1016/s2352-3026(22)00372-6
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Abstract

Background Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown activity in treating relapsed or refractory multiple myeloma; however, relapse is still common, and new targets are needed. We aimed to assess the activity and safety profile of G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma. Methods POLARIS was a first-in-human, single-centre, single-arm, phase 1 trial of GPRC5D-targeted CAR T cells (OriCAR-017) done at the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. Eligible patients were adults aged 18-75 years with a diagnosis of relapsed or refractory multiple myeloma and an ECOG performance status of 0-2, had GPRC5D expression in bone marrow plasma cells greater than 20% or were positive for GPRC5D by immunohistochemistry, and had received at least three previous lines of treatment including proteasome inhibitors, immunomodulatory drugs, and chemotherapy. Patients were consecutively assigned to receive a single dose of intravenous OriCAR-017 at 1 × 10 6 CAR T cells per kg, 3 × 10 6 CAR T cells per kg, or 6 × 10 6 CAR T cells per kg in the dose-escalation phase. In the expansion phase, patients received the recommended phase 2 dose. Recruitment to the expansion phase terminated early due to the COVID-19 pandemic on May 1, 2022. The primary endpoints were safety, the maximum tolerated dose and the recommended phase 2 dose. Safety and activity analyses included all patients who received OriCAR-017. This trial is registered with ClinicalTrials.gov, NCT05016778. This trial has been completed and is entering long-term follow-up. Findings Between June 9, 2021, and Feb 28, 2022, we recruited 13 patients for inclusion into the study. One patient was excluded because of GPRC5D negativity and two patients discontinued after apheresis because of rapid progression. Nine patients were assigned to the dose escalation phase (three received 1 × 10 6 CAR T cells per kg, three received 3 × 10 6 CAR T cells per kg, and three received 6 × 10 6 CAR T cells per kg). The maximum tolerated dose was not identified, because no dose-limiting toxic effects were observed. On the basis of safety and preliminary activity, the recommended phase 2 dose was set at 3 × 10 6 CAR T cells per kg, which was received by one additional patient in the dose expansion phase. Five patients (50%) were female, five (50%) were male, and all were Chinese. Five patients (50%) were previously treated with BCMA-targeted CAR T-cell therapy. Median follow-up was 238 days (IQR 182-307). There were no serious adverse events and no treatment-related deaths. The most common grade 3 or worse adverse events were haematological, including neutropenia (ten [100%] of ten patients), thrombocytopenia (nine [90%]), leukopenia (nine [90%]), and anaemia (seven [70%]). All patients had cytokine release syndrome (nine [90%] grade 1 and one [10%] grade 2). No neurological toxic effects were reported. Ten (100%) of ten patients had an overall response, of whom six (60%) had a stringent complete response and four (40%) had very good partial response. Two patients discontinued due to disease progression (one GPRC5D-positive patient in the middle-dose group and one GPRC5D-negative patient in the low-dose group). Interpretation The results of this study suggest that GPRC5D is an active target for immunotherapy in multiple myeloma. GPRC5D-targeted CAR T-cell therapy is a promising treatment modality for patients with relapsed or refractory multiple myeloma and deserves further testing. Funding OriCell Therapeutics.

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  • CAR-T cells targeting GPRC5D, CD19, CD38, CD138, CS1, and NKG2D are under exploration for MM treatment.

    “Several CAR-T cells targeting antigens, such an GPRC5D [229–231], CD19 [232, 233], CD38 [234–236], CD138 [237], CS1 [238–240] and NKG2D [241, 242] are also under exploration for their efficacy in MM treatment.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [231]

  • The observed adverse events with OriCAR-017 included neutropenia (100%), thrombocytopenia (90%), leukopenia (90%), and anemia (70%).

    “The observed adverse events included neutropenia (100%), thrombocytopenia (90%), leukopenia (90%), and anemia (70%).”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [231]

  • CRS was observed in all OriCAR-017 patients, with 90% classified as grade 1 and 10% as grade 2.

    “CRS was observed in all patients, with 90% classified as grade 1 and 10% as grade 2.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [231]

  • No neurotoxicity was reported with OriCAR-017.

    “No neurotoxicity was reported.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [231]

  • The therapy demonstrated a good response rate, with 60% of patients achieving sCR and 40% achieving VGPR.

    “The therapy demonstrated a good response rate, with 60% of patients achieving sCR and 40% achieving VGPR.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [231]

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Authors
Zhang, M., Wei, G., Zhou, L., Zhou, J., Chen, S., Zhang, W., Wang, D., Luo, X., Cui, J., Huang, S., Fu, S., Zhou, X., Tang, Y., Ding, X., Kuang, J., He, X. P., Hu, Y., & Huang, H.
Affiliations
First Affiliated Hospital Zhejiang University (CN)
Corresponding author
Huang, He
ORCID
Venue
The Lancet Haematology
Publisher
Elsevier BV
Published
2023-02
Volume
10
Issue
2
Pages
e107-e116
ISSN
2352-3026 (ISSN-L)
DOI
10.1016/s2352-3026(22)00372-6
OpenAlex
W4318922300
Cited by
166
References
24
Citations by year
2026: 20 · 2025: 47 · 2024: 67 · 2023: 32
FWCI
20.25
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Haematology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
relapsed/refractory multiple myeloma, CAR T-cell therapy, dose escalation, maximum tolerated dose, recommended phase 2 dose, safety, myeloma cells
MeSH terms
COVID-19, Adult, Anemia, Female, Humans, Male, Multiple Myeloma, Neoplasm Recurrence, Local, T-Lymphocytes, Thrombocytopenia, Receptors, G-Protein-Coupled, B-Cell Maturation Antigen, Pandemics

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