Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

中文翻译：

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一种针对多发性骨髓瘤的复合嵌合抗原受体策略。

使用针对多发性骨髓瘤的嵌合抗原受体（CARs）的当前临床结果在根除大面积疾病方面显示出希望。但是，由于抗原阳性或阴性细胞的重新出现，这些抗BCMA（CD269）CAR在治疗后观察到复发是一种常见现象。因此，发展针对目标抗原损失和增加效应细胞持久性的CAR设计的改进代表了关键的需求。在这里，我们报告具有两个完整和独立的CAR受体的CAR T细胞对多种骨髓瘤抗原BCMA和CS1的抗肿瘤活性。我们确定了所得的化合物CAR（cCAR）T细胞具有针对每个靶抗原群体的一致，有效和定向的细胞毒性。使用多发性骨髓瘤和混合细胞群的小鼠模型，与单一表达的CAR T细胞相比，我们通过针对多种人群的定向细胞毒性进一步显示了优异的体内存活率。这些发现表明，针对骨髓瘤细胞的BCMA和CS1复合靶向可能是增强针对骨髓瘤大块疾病的反应和启动更广泛的CAR治疗的有效策略。