MZB1 TCR-Like CAR T-Cell Therapy Yields Antitumor Activity in Multiple Myeloma and Waldenström Macroglobulinemia

Elena Maroto-Martin, PhD

MZB1-targeted TCR-like CAR T-cell therapy has demonstrated potent, specific in vitro, ex vitro, and in vivo antitumor activity against this complex in preclinical models of multiple myeloma and Waldenström Macroglobulinemia, according to Elena Maroto-Martin, PhD.

“We performed an integrated analysis, combining transcriptomic and proteomic data from myeloma cell lines, patient cells, and healthy tissues, and we identified MZB1 as being highly expressed on myeloma cells,” Maroto-Martin said in an interview with OncLive®.

Unlike traditional CAR T-cell therapies FDA approved for multiple myeloma, such as idecabtagene vicleucel (ide-cel; Abecma)or ciltacabtagene autoleucel (cilta-cel; Carvykti), these TCR-like CAR T cells can recognize and bind to intracellular antigens presented on the cell surface by major histocompatibility complex (MHC) molecules, Maroto-Martin explained. This expands the applicability of such a therapy in malignancies where there are a limited number of tumor-specific surface antigens that can be targeted by current agents.

During the interview, Maroto-Martin detailed the currently available CAR T-cell therapies and the mechanism of action of this TCR-like CAR T-cell therapy; expanded on the rationale for evaluating the novel CAR T-cell therapy in multiple myeloma and Waldenström macroglobulinemia; and highlighted the efficacy data and next steps for this research.

Maroto-Martin is a postdoctoral research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: What are some of the benefits and limitations seen with approved CAR T-cell therapies for patients with multiple myeloma?

Maroto-Martin: Regarding benefits, there is [typically] a high initial response seen with ide-cel or cilta-cel. These agents are working well and show deep and rapid responses. Regarding the limitations, some toxicities like cytokine release syndrome [CRS] or immune effector cell-associated neurotoxicity syndrome [ICANS] are still common, but these are very manageable. However, one of the biggest limitations is that even if the responses are good at the beginning, most patients still eventually have relapsed disease.

What is unique about the mechanism of action of MZB1 TCR-like CAR T-cell therapy?

MZB1 is a protein, and it plays an important role in cancer antibody production. Conventional CAR T-cell therapies are unable to recognize MZB1; therefore, our strategy was to target intracellular targets through the MHC. This mimics the natural behavior of a T-cell receptor. In this case, myeloma cells would process MZB1 internally. The MZB1 peptides would be presented in the HLA-A*02:01 plasma molecules, and our MZB1 CAR T-cells will be able to recognize these MZB1 peptides on the surface of the cells through the HLA-A*02:01 complex.

How might this therapy address an unmet need for patients with multiple myeloma and Waldenström macroglobulinemia?

We know that CAR T-cell therapies are improving patient outcomes, but one of the major limitations is the availability of tumor-specific antigens that are expressed on the cell surface. Based on that, we know that in multiple myeloma, we have BCMA- and GPRC5D-targeted therapies that are doing a great job. However, if we think about this from the standpoint of Waldenström macroglobulinemia, there are currently no available or approved CAR T-cell therapies for those patients. Therefore, we aimed to identify novel intracellular targets that we could use with this strategy.

What were the key findings from this study?

We were able to generate a potent disease control rate, like CAR T-cell therapy, and it worked against multiple myeloma and Waldenström macroglobulinemia. We saw very good killing and specificity against MZB1- and HLA-A*02:01-[positive] cells, both in myeloma and Waldenström Macroglobulinemia. We also saw good efficacy against primary myeloma and Waldenström Macroglobulinemia cells. More importantly, in vivo, we also saw the eradication of the tumor.

What are the next steps for developing this therapy?

Right now, we are working on developing bispecific antibodies against MZB1 MHC in the tumor and CD3 of the T-cells. We would also like to explore combinations with other antigens that will allow us to have more therapeutic options. Beyond CAR T-cell therapy, we could also consider bispecific antibodies as an alternative therapy.

References

Maroto-Martin E, He M, Zhao Y, et al. MZB1 TCR-like CAR T cell therapy: a new weapon in the war against multiple myeloma and Waldenström Macroglobulinemia. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract 6115.