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Cited by 222CAR-T cell therapy researchMultiple Myeloma Research and TreatmentsImmunotherapy and Immune Responses

A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma

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Mei, Heng, Li, Chenggong, Jiang, Huiwen, Zhao, Xinying, Huang, Zhiping, Jin, Dan, Guo, Tao, Kou, Haiming +14 more·2021·Journal of Hematology & Oncology
DOI 10.1186/s13045-021-01170-7PMC PMC8501733
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Abstract

Background: BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods: We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results: BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion: Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration: Chictr.org.cn ChiCTR1800018143.

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Crossref · 10.1186/s13045-021-01170-7

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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 [234]

  • In the phase I trial of BM38 CAR-T therapy, 87% (20/23) patients achieved a clinical response, and sCR was 52% (12/23).

    “The phase I trial evaluating the efficacy and safety of BM38 CAR-T therapy, 87% (20/23) patients achieved a clinical response, and 20 responders achieved MRD-negativity, sCR was 52% (12/23).”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [234]

  • The median follow-up was 9.0 months, and the mPFS was 17.2 months.

    “The median follow-up was 9.0 months (range 0.5 to 18.5), the mPFS was 17.2 months.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [234]

  • Hematologic toxicities with BM38 included neutropenia (96%), leukopenia (87%), anemia (43%), and thrombocytopenia (61%).

    “Hematologic toxicities were common, including neutropenia (96%), leukopenia (87%), anemia (43%) and thrombocytopenia (61%) [234].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [234]

  • CRS occurred in 87% (20/23) of patients, and grade ≥ 3 CRS occurred in 22% of patients.

    “The CRS occurred in 87% (20/23) of patients and grade ≥ 3 CRS occurred in 22% of patients.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [234]

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Authors
Mei, H., Li, C., Jiang, H., Zhao, X., Huang, Z., Jin, D., Guo, T., Kou, H., Liu, L., Tang, L., Yin, P., Wang, Z., Ai, L., Ke, S., Xia, Y., Deng, J., Chen, L., Cai, L., Sun, C., Xia, L., Hua, G., & Hu, Y.
Affiliations
  • Wuhan Union Hospital (CN)
  • Yangtze University (CN)
  • Huazhong University of Science and Technology (CN)
Corresponding author
  • Mei, Heng
  • Hu, Yu
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2021-10-09
Volume
14
Issue
1
Pages
161-161
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-021-01170-7
PMC
PMC8501733
OpenAlex
W3206783250
Cited by
222
References
11
Citations by year
2026: 25 · 2025: 46 · 2024: 64 · 2023: 45 · 2022: 39 · 2021: 3
FWCI
14.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
national natural science foundation of china (81873434, 81770132)
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
bispecific CAR T cells, BCMA, CD38, relapsed/refractory multiple myeloma, cytokine release syndrome, minimal residual disease, extramedullary plasmacytoma, CAR T cell persistence, hematologic toxicity
MeSH terms
Receptors, Chimeric Antigen, Adult, Aged, Animals, Female, Humans, Male, Middle Aged, Multiple Myeloma, Neoplasm Recurrence, Local, Immunotherapy, Adoptive, Cell Line, Tumor, Mice, ADP-ribosyl Cyclase 1, B-Cell Maturation Antigen, Molecular Docking Simulation

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