全人抗体在维持对肿瘤杀伤的同时降低"off tumor"毒性

A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity

Summary:
Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate “on-target” toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and “on-target off-tumor” toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.

全人抗体在维持对肿瘤杀伤的同时降低"off tumor"毒性
摘要：
嵌合抗原受体(CARs)能够指导T细胞以一种HLA不相关的方式对抗表达特殊抗原的肿瘤。近日，我们已经使用高亲和性的鼠单链抗原可变区域(scFvs)构建了多种CARs，在体内有免疫原性，具有间接靶向毒性的潜在能力。这里，我们开发并评估了一种完全人类CAR，由人C4叶酸受体α（αFR）的特异性scFv和T细胞细胞内的信号域组成。人类T细胞转导表达C4 CAR，特异性分泌促炎症反应细胞活素，当和表达αFR的肿瘤在体内一起培养时，具有细胞毒性功能。靶向C4 CAR T细胞过继治疗导致了在异种小鼠体内建立的人卵巢癌细胞大量的衰退。相对于以鼠MOv19 scFv为基础的αFR CAR，C4 CAR-T细胞介导的抗肿瘤杀伤活性在体内和体外相当，但是对低表达αFR的正常细胞，具有较低的亲和性，而且显示了减弱的识别性。因此，具有中等亲和力，表达一个完整的人CAR T细胞在体外和体内能有效杀伤肿瘤，而且也许能够克服转基因免疫原性和“靶向非肿瘤”毒性，这些出现在使用鼠来源的高亲和性scFvs的CAR-T试验中的不良事件。