Combining BCMA-targeting CAR-T with TCR-engineered T-cell therapy to prevent immune escape of multiple myeloma.

Chimeric antigen receptor (CAR) T cell therapy targeting BCMA can induce deep remissions in relapsed/refractory multiple myeloma (MM), however, relapse due to antigen escape is common. To prevent antigen escape, multi-antigen-targeting strategies are being developed, but alternative CAR-targets are limitedly available and harbor similar risk of antigen escape. Here, we propose a multi-antigen-targeting strategy incorporating TCR-engineered (eTCR) T cells, as the ability of TCR-engineered T cells to target intracellular protein derived antigens broadens the spectrum of safely targetable antigens. When subjecting primary MM cells to BCMA targeting CAR-T cells, or to TCR engineered T cells targeting an HLA-B7 restricted peptide derived from the MM-essential transcription factor BOB1, both CAR T and eTCR T cells efficiently lysed primary MM. Intriguingly however, we observed that MM cells surviving in a suboptimal E:T ratio downmodulated BCMA, whereas HLA expression was increased. Furthermore, in an in vivo immune escape model of MM, only a combination of BCMA-CAR-T cells with BOB1-TCR engineered T cells could completely clear tumors from bone marrow of mice bearing heterogenous tumors, whereas single-agent treatment led to progressive outgrowth of immune escaped MM. Collectively, we provide a preclinical rationale of combining HLA-dependent and -independent targeting for the cellular therapy of MM.