Dr Maroto-Martin on the Mechanism of MZB1-Targeted CAR T-Cell Therapy in Myeloma and Waldenström Macroglobulinemia

“MZB1 is an endoplasmic reticulum protein. It plays an important role in cancer [cell] homeostasis and antibody production. Conventional CAR T cells [are] not able to recognize MZB1, so our strategy was [to target] intracellular [antigens] through [the major] histocompatibility complex. Basically, it's mimicks the natural behavior of a T-cell receptor.”

Elena Maroto-Martin, PhD, a postdoctoral clinical research scientist at Dana-Farber Cancer Institute, discussed the mechanism of action and therapeutic rationale for evaluating 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 described the strategy of targeting intracellular tumor-associated antigens through the use of peptide-HLA complexes, focusing on MZB1, an endoplasmic reticulum–resident protein involved in antibody production and plasma cell biology. Although MZB1 is not expressed on the cell surface, it can be processed intracellularly and presented on the surface of tumor cells via MHC class I molecules, particularly HLA-A alleles.

To exploit this mechanism, investigators designed a TCR-like CAR T-cell construct capable of recognizing the MZB1 peptide presented in the context of HLA-A02:01. Unlike conventional CAR T cells, which are limited to targeting surface proteins, this approach mimics the native behavior of T-cell receptors, enabling the recognition of intracellular antigens via peptide-HLA presentation. Using computational prediction tools, the team identified MZB1-derived peptides predicted to bind HLA-A02:01.

Patient-derived T cells were transduced with lentiviral vectors encoding the MZB1-specific TCR-like CAR construct. Maroto-Martin explained that the resulting TCR-like CAR T cells demonstrated selective cytotoxicity against multiple myeloma and Waldenström macroglobulinemia cells expressing the MZB1/HLA-A2 complex. These cells also exhibited cross-reactivity with other HLA alleles, including HLA-A24 and HLA-A23.

In vitro and ex vivo studies showed that the MZB1-targeted, TCR-like CAR T cells efficiently eliminated HLA-matched tumor cells, while in vivo experiments using a humanized mouse model showed antitumor activity and prolonged survival. The specificity and potency of the construct support further development, Maroto-Martin noted.