嵌合抗原受体（CAR）T细胞治疗针对BCMA可诱导复发/难治性多发性骨髓瘤（MM）的深度缓解，然而，抗原逃逸导致复发是常见的。为了预防抗原逃逸，正在开发多抗原靶向策略，但备选CAR靶点有限，并且存在着类似的抗原逃逸风险。在这里，我们提出了一种结合TCR工程化（eTCR）T细胞的多抗原靶向策略，因为TCR工程化T细胞对靶向细胞内蛋白质衍生抗原的能力拓宽了可安全靶向的抗原谱。当将原发性MM细胞暴露于针对BCMA的CAR-T细胞或针对来自MM必需转录因子BOB1的HLA-B7限制性肽段的TCR工程化T细胞时，CAR T细胞和eTCR T细胞均有效溶解了原发性MM。然而，耐受不佳的E：T比下存活的MM细胞表达下调BCMA，而HLA表达增加。此外，在MM的体内免疫逃逸模型中，仅BCMA-CAR-T细胞与BOB1-TCR工程化T细胞的组合能够完全清除携带异质性肿瘤的小鼠骨髓中的肿瘤，而单一药物治疗导致免疫逃逸MM的逐渐增长。总的来说，我们提供了结合HLA依赖性和非依赖性靶向来治疗MM的细胞疗法的临床前理论依据。Copyright © 2023 American Society of Hematology.

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.Copyright © 2023 American Society of Hematology.