Dr Maroto-Martin on the Preliminary Efficacy of MZB1 TCR-Like CAR T-Cell Therapy in Myeloma

“We were able to generate a potent TCR-like CAR T-cell therapy which [displayed efficacy] against multiple myeloma and Waldenström macroglobulinemia [cells]. We saw very good [tumor cell] killing and specificity against MZB1/HLA-A2–positive cells. We [also saw] efficacy against primary multiple myeloma and Waldenström macroglobulinemia cells. Importantly, in vivo, we saw the eradication of tumor [cells] and prolonged overall survival.”

Elena Maroto-Martin, PhD, postdoctoral clinical research scientist, Dana-Farber Cancer Institute, discussed early efficacy data with an MZB1-targeted T-cell receptor (TCR)–like CAR T-cell therapy in preclinical models of multiple myeloma and Waldenström macroglobulinemia.

During the 2025 AACR Annual Meeting, Maroto-Martin presented data from a preclinical study in which investigators identified the intracellular protein MZB1 as being highly expressed on multiple myeloma cells in the presence of HLA-A*02:01. The study authors used computational prediction to identify potential putative peptides of MZB1 that could be presented alongside HLA-A*02:01. They then synthesized antibodies specific for the MZB1/HLA-A2 complex using the sequences of 2 clones which showed higher affinity for the complex.

They then generated a potent TCR-like CAR T-cell therapy targeting MZB1, Maroto-Martin explained. To create the TCR-like CAR T-cell therapy, investigators transduced patients’ T cells with lentivectors containing MZB1.

Findings from the study demonstrated that the agent had the ability to specifically bind to multiple myeloma and Waldenström macroglobulinemia cells that were HLA-A2/MZB1 positive, Maroto-Martin said. The agent produced encouraging antitumor activity by efficiently eliminating primary multiple myeloma and Waldenström macroglobulinemia cells, Maroto-Martin noted. The TCR-like CAR T-cell therapy also displayed HLA cross-reactivity, recognizing and eliminating MZB1-positive cells presented by other HLA alleles, such as HLA-A24/A23.

Importantly, the agent produced in vivo efficacy and prolonged survival in a humanized model of multiple myeloma, Maroto-Martin concluded. The TCR-like CAR T-cell therapy also showed potent and specific antitumor activity in vitro and ex vivo against the HLA-A2/MZB1 complex on multiple myeloma and Waldenström macroglobulinemia cells. The study authors concluded that their findings provided the rationale for the development of similar therapies directed against other intracellular targets in multiple myeloma and additional B-cell malignancies.