PDF(Pubmed)
Abstract：
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.
摘要：
在大多数癌症中，嵌合抗原受体（CAR）工程化T细胞疗法的疗效欠佳。需要进一步改善其治疗作用。然而,增强抗肿瘤T细胞反应不可避免地会增加与单核细胞来源的白介素-6(IL-6)相关的细胞因子释放综合征的风险.因此，同时提高疗效和安全性的方法是必要的.这里,我们开发了一种嵌合细胞因子受体,该受体由GP130和IL6RA的细胞外结构域与IL-7R突变体的跨膜和细胞质结构域连接组成,该突变体组成性激活JAK-STAT途径(G6/7R或G6/7R-M452L).具有G6/7R的CAR-T细胞在体外有效吸收和降解单核细胞来源的IL-6。表达G6/7R的CAR-T细胞在体内表现出优异的扩增和持久性，在液体和实体瘤小鼠模型中产生持久的抗肿瘤反应。我们的策略可以广泛应用于CAR-T细胞治疗，以提高其疗效和安全性，与靶抗原无关。
