Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo https://www.science.org/doi/10.1126/scitranslmed.adg7962 Editor’s summary Taking a STAb at cellular therapy. Multiple myeloma is a hematological cancer with limited treatment options, particularly after relapse. Chimeric antigen receptor (CAR) T cells are being explored for multiple myeloma, much like for other hematological malignancies, but patients still relapse. Here, Díez-Alonso et al. developed STAb-T cells, which, rather than express a CAR, secrete T cell–engaging antibodies targeting B cell maturation antigen (BCMA) and CD3. The authors compared STAb-T cells with traditional CAR-T cells in vitro and in vivo, showing that the STAb-T cells more effectively killed target cells at low frequencies and were resistant to inhibition mediated by soluble BCMA released from myeloma cells, preventing immune escape. This translated to improved in vivo efficacy in a murine multiple myeloma model, supporting further development of BCMA-specific STAb-T cells as a therapeutic for this and other hematological malignancies. —Courtney Malo Abstract Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.