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.

中文翻译：

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工程化 T 细胞分泌抗 BCMA T 细胞接合剂，控制多发性骨髓瘤并促进体内免疫记忆

多发性骨髓瘤是成人中第二常见的血液恶性肿瘤，并且仍然是一种无法治愈的疾病。B细胞成熟抗原（BCMA）定向免疫疗法，包括带有嵌合抗原受体（CAR）的T细胞和全身注射的双特异性T细胞接合剂（TCE），已显示出显着的临床活性，并且多个产品已获得市场批准。然而，尽管结果有希望，但大多数患者最终会变得难治和复发，这凸显了对替代策略的需要。分泌 TCE 抗体 (STAb) 的工程化 T 细胞代表了一种有前景的策略，它结合了过继细胞疗法和双特异性抗体的优点。在这里，我们进行了一项全面的临床前研究，比较了在模拟所发现条件的 T 细胞限制实验环境中表达第二代抗 BCMA CAR (CAR-T) 或分泌 BCMAxCD3 TCE (STAb-T) 的 T 细胞的治疗潜力复发/难治性多发性骨髓瘤患者。STab-T细胞以极低的效应子与靶标比率募集T细胞活性，并且对细胞表面释放的可溶性BCMA介导的抑制具有抵抗力，从而增强细胞毒性反应并防止多发性骨髓瘤细胞在体外的免疫逃逸。这些优势导致 STAb-T 细胞在体内强劲扩增和持久存在，产生长效记忆 BCMA 特异性反应，可以控制异种移植模型中的多发性骨髓瘤进展，性能优于传统 CAR-T 细胞。这些有希望的临床前结果鼓励对复发/难治性多发性骨髓瘤的 BCMA-STAb-T 细胞方法进行临床测试。