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

"We know that CAR T cells are [improving] patient outcomes, but one of the major limitations is the availability of tumor-specific antigens that are expressed on the cell surface. We aimed to identify novel intracellular targets that we could use with this novel strategy."

Elena Maroto-Martin, PhD, a research fellow at Dana-Farber Cancer Institute, discussed how TCR-like CAR T-cell therapy could address the limitations of current CAR T-cell therapies for multiple myeloma and Waldenström macroglobulinemia.

Maroto-Martin and colleagues designed a novel generation of CAR T cells designed to overcome a key limitation of current CAR T-cell therapies: the requirement for tumor-specific surface antigens. Traditional CAR T cells are limited to recognizing extracellular epitopes, which restricts their applicability in malignancies where few surface-expressed tumor-specific targets exist, Maroto-Martin explained.

To address this, the investigators engineered TCR-like CAR T cells capable of recognizing intracellular antigens presented on the cell surface in the context of major histocompatibility complex molecules, Maroto-Martin detailed. This expands the potential target repertoire for CAR T-cell therapy by allowing the recognition of intracellular tumor-associated proteins, she said.

The group performed integrated transcriptomic and proteomic analyses of multiple myeloma cell lines, patient-derived myeloma cells, and healthy tissue to identify intracellular targets with high tumor specificity and limited normal tissue expression. Through this approach, they identified the intracellular MZB1 protein as a potential antigen, particularly when complexed with the HLA-A*02:01 allele.

Preclinical findings presented at the 2024 AACR Annual Meetingdemonstrated that these MZB1/HLA-A*02:01-targeting TCR-like CAR T cells exhibited potent and specific antitumor activity in vitro, ex vivo, and in vivo against both multiple myeloma and Waldenström macroglobulinemia models. These results underscore the therapeutic potential of targeting intracellular antigens via TCR-like CAR T-cell constructs and establish a translational framework for extending this strategy to other intracellular targets across hematologic malignancies and solid tumors.