肿瘤细胞治疗研究
英文原题：Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells.
Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells.
嵌合抗原受体（CAR）工程化 T 细胞疗法在大多数肿瘤中疗效欠佳，需要进一步改进其治疗作用。
嵌合抗原受体（CAR）工程化 T 细胞疗法对多数癌症的疗效仍不理想，亟需进一步提高治疗作用。然而，增强抗肿瘤 T 细胞应答不可避免地会增加细胞因子释放综合征风险，该综合征与单核细胞来源的白细胞介素-6（IL-6）相关。因此，需要同时改善疗效和安全性的策略。本研究开发了一种嵌合细胞因子受体，由 GP130 和 IL6RA 的胞外结构域与 IL-7R 突变体的跨膜及胞内结构域相连组成；该受体可持续激活 JAK-STAT 通路，称为 G6/7R 或 G6/7R-M452L。表达 G6/7R 的 CAR-T 细胞可在体外有效吸收并降解单核细胞来源的 IL-6。表达 G6/7R 的 CAR-T 细胞在体内扩增和持久性更强，并在液体瘤和实体瘤小鼠模型中产生持久抗肿瘤应答。无论靶抗原为何，该策略均可能广泛用于 CAR-T 治疗，以提高疗效和安全性。
The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.
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