Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation

Genetic Disruption of Blimp-1 Drastically Augments the Persistence and Anti-Tumour Efficacy of BCMA-Targeting CAR-T Cells

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

Preclinical Activity of Allogeneic CS1-Specific CAR T-Cells (UCARTCS1) in Multiple Myeloma

Targeting of the CD161 Inhibitory Receptor Enhances Bone Marrow-Resident Memory CD8+ T Cell-Mediated Immunity Against Multiple Myeloma

Chimeric Antigen Receptor (CAR) T Cells Specific for CD229: A Potentially Curative Approach for Multiple Myeloma

A TCR-like CAR T Cell Therapy for the Treatment of MZB1 Positive Multiple Myeloma and Other B-Cell Malignancies

DAP10 integration in CAR-T cells enhances the killing of heterogeneous tumors by harnessing endogenous NKG2D

Biallelic Loss of BCMA Triggers Resistance to Anti-BCMA CAR T Cell Therapy in Multiple Myeloma

New Antibcma-CAR for Multiple Myeloma

B-cell maturation antigen chimeric antigen receptor T-cell re-expansion in a patient with myeloma following salvage programmed cell death protein 1 inhibitor-based combination therapy.

Multiple myeloma (MM) is a plasma cell neoplasm accounting for 10% of all hematological tumors. CAR-T cell therapies have demonstrated unprecedented response rates, resulting in the FDA approval of two BCMA CAR-T products. Despite good initial responses, relapses are common and caused by tumor antigen loss and/or CAR T cell exhaustion. One way to overcome tumor antigen loss is to target a different cancer antigen. However, a limited number of cancer-specific proteins are expressed on the cell surface, where they are accessible to immunotherapies. Normal cells ubiquitously express MHC Class I molecules, which present fragments of cellular proteins to the immune system. Here, we have developed a new generation of CAR T cells able to recognize intracellular antigens presented by an MHC molecule on the cell surface. To identify antigens for a TCR-like CAR T therapy, we combined transcriptomic and proteomic data from MM cell lines, MM patients, and healthy tissues. We found that the intracellular protein MZB1, which is involved in the maturation and function of plasma cells, is highly expressed in MM cells as well as a small subset of B cells including Waldenström Macroglobulinemia (WM) and B-cell lymphoma cells. By computational prediction, we identified putative MZB1 peptides that can be presented in the context of HLA-A*02:01, the most frequent HLA allele worldwide. We used a human scFv antibody yeast surface display library to select monoclonal antibody clones specific to the MZB1:HLA-A*02 complex. By performing binding affinity analysis by flow cytometry in a large panel of MM and WM cell lines with differential expression of MZB1 and/or HLA-A2, we selected two clones with higher binding affinity to the HLA-A2/MZB1 positive cells that were further utilized for CAR design. CAR constructs containing the MZB1-A2 scFv, a 41BB co-stimulatory domain and CD3z signaling domain were generated. MZB1 CAR T cells showed significant cytotoxicity against MZB1+ HLA-A2+ MM and WM cells compared to untransduced T cells, but not against HLA-A2 and/or MZB1 negative cells. Additionally, MZB1 CAR T cells showed higher expression of activation markers and significant increased release of IFNy and Granzyme A/B when co-cultured with MZB1+ HLA-A2+ cells, suggesting enhanced antitumor immune responses. To validate the translational potential of MZB1 CAR T cells we confirmed their tumor-killing activity ex vivo across primary MM cells from ND and relapsed MM patients. Importantly, in vivo administration of 1x107 CAR T cells reduced myeloma burden in a human MM disseminated murine model. In conclusion, we have generated TCR-like CAR T cells that show potent and specific in vitro, ex vivo and in vivo antitumor efficacy against MZB1/HLA-A*02:01 complex on the surface of MM and WM cells. This study provides the logic and framework for similar therapies to be developed against other intracellular targets in MM and other cancers. Citation Format: Elena Maroto-Martin, Marina He, Yingjie Zhao, Jessica Encinas, Sara M. Kolhatkar, Roberto Garcia-Vicente, Mubin Tarannum, Zachary R. Hunter, Rizwan Romee, Mehmet K. Samur, Mariateresa Fulciniti, Jianzhu Chen, Nikhil C. Munshi. MZB1 TCR-like CAR T cell therapy, a new weapon in the war against multiple myeloma and waldenström macroglobulinemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6115.

CS1-Specific Chimeric Antigen Receptor (CAR)-Engineered NK Cells and T Cells Enhance In Vitro and In Vivo Anti-Tumor Activity Against Human Multiple Myeloma

A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignances

BackgroundBCMA-targeted chimeric antigen receptor (CAR)T-cell therapy promotes transient recovery in patients with multiple myeloma, but relapses occurs commonly. GPRC5D, a surface receptor that is highly expressed in bone marrow samples...

CD38 Specific Chimeric Antigen Receptor KHYG-1 Natural Killer Cells: A Potential “Off the Shelf” Therapy for Multiple Myeloma