Bispecific CAR-T vs. BCMA-Specific CAR-T: Advancing Treatment for Relapsed/Refractory Multiple Myeloma

Nigmat Rahim

doi:10.54097/wvmnsh51

Authors

Nigmat Rahim

DOI:

https://doi.org/10.54097/wvmnsh51

Keywords:

Multiple myeloma, CAR T-cell therapy, B-cell maturation antigen (BCMA), bispecific CAR-T, antigen escape.

Abstract

Multiple myeloma (MM), despite therapeutic advances, remains an incurable disease. Therefore, the most patients eventually progress to relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown remarkable efficacy in RRMM. However, limitations such as antigen escape, tumor heterogeneity, and T-cell exhaustion led to relapse. This review provides a comprehensive perspective on the transformative potential of bispecific CAR-T cell therapy as a promising strategy to overcome resistance and improve outcomes for patients with RRMM. The mechanisms of resistance to BCMA-targeted CAR-T therapy are comprehensively analyzed and categorized into BCMA-positive and BCMA-negative relapse/refractory mechanisms. The MIF/CD74 pathway as a potential contributor to BCMA CAR-T resistance was supported by single-cell RNA sequencing data and previous studies. The mechanistic advantages of dual-target are explored dual target CAR-T can prevent antigen escape and enhance T-cell activation. Clinical review of clinical trial data demonstrates the superior efficacy of bispecific CAR-T compared to BCMA CAR-T, including higher drug effect and more manageable side effects.

Downloads

Download data is not yet available.

References

[1] Van de Donk NWCJ, Pawlyn C., Yong K. L. Multiple myeloma. Lancet, 2021.

[2] Cowan A. J., Green D. J., Kwok M., et al. Diagnosis and Management of Multiple Myeloma: A Review. Jama, 2022.

[3] Malard F., Neri P., Bahlis N. J., et al. Multiple myeloma. Nat Rev Dis Primers, 2024.

[4] Leypoldt L. B., Tichy D., Besemer B., et al. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma. J Clin Oncol, 2024.

[5] Xu Jia, Luo Wenjing, Liao Danying, et al. Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. Leukemia, 2024.

[6] Shi Ming, Wang Jiaojiao, Huang Hongming, et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial. Nat Commun, 2024.

[7] Zhou Dian, Sun Qian, Xia Jieyun, et al. Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial. Lancet Haematol, 2024.

[8] Wang Zehua, Chen Chen, Wang Lei, et al. Chimeric antigen receptor T-cell therapy for multiple myeloma. Front Immunol, 2022.

[9] Li Wei, Zhang Binglei, Cao Weijie, et al. Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing. Exp Hematol Oncol, 2023.

[10] Chan Wing Keung, Williams Jessica, Sorathia Kinnari, et al. A novel CAR-T cell product targeting CD74 is an effective therapeutic approach in preclinical mantle cell lymphoma models. Exp Hematol Oncol, 2023.

[11] Chen Xinzhuo, Huang Renhua, Wang Huiping, et al. Single Cell RNA-Seq Analysis Revealed MIF/CD74 Pathway Determinants of BCMA CART Resistance in Relapsed/Refractory Multiple Myeloma. Blood, 2024.

[12] Da Vià M. C., Dietrich O., Truger M., et al. Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma. Nat Med, 2021.

[13] Samur M. K., Fulciniti M., Aktas Samur A., et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun, 2021.

[14] Golubovskaya V., Zhou Hua, Li Feng, et al. Novel CS1 CAR-T Cells and Bispecific CS1-BCMA CAR-T Cells Effectively Target Multiple Myeloma. Biomedicines, 2021.

[15] Korst Clbm, O'Neill C., Bruins W. S. C., et al. Preclinical activity of allogeneic SLAMF7-specific CAR T-cells (UCARTCS1) in multiple myeloma. J Immunother Cancer, 2024.

[16] Wang Weijia, He Shanzhi, Zhang Wenli, et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial. Ann Rheum Dis, 2024.

[17] Xiang Xinrong, He Qiao, Ou Yang, et al. Efficacy and Safety of CAR-Modified T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Prospective Clinical Trials. Front Pharmacol, 2020.

[18] Cappell K. M., Kochenderfer J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol, 2023.

[19] Delforge Michel, Baz Rachid C., Cavo Michele, et al. KarMMa-3: A Phase 3 Study of Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy Vs Standard Regimens in Relapsed and Refractory Multiple Myeloma. Blood, 2020.

[20] Mei Heng, Li Chenggong, Jiang Huiwen, et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma. J Hematol Oncol, 2021.

[21] Tang Yuanyan, Yin Haisen, Zhao Xinying, et al. High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma. J Exp Clin Cancer Res, 2022.

[22] Wang Ying, Cao Jiang, Gu Weiying, et al. Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma. J Clin Oncol, 2022.

[23] Qiang Wanting, Lu Jing, Jia Yanchun, et al. B-Cell Maturation Antigen/CD19 Dual-Targeting Immunotherapy in Newly Diagnosed Multiple Myeloma. JAMA Oncol, 2024.