嵌合抗原受体 (CAR) 和 T 细胞受体 (TCR) T 细胞疗法对部分实体瘤患者有效，但需要新的方法来普遍改善患者的治疗效果。在这里，我们开发了一种技术，利用 IL-15 和 IL-21（两种常见的细胞因子受体伽马链家族成员，对 T 细胞和其他淋巴细胞具有独特的多效性作用）的协同作用，来增强过继性 T-细胞的功效。我们设计了诱导膜束缚 IL-15、IL-21 或 IL-15/IL-21 组成型表达的载体。我们使用针对儿童和成人实体瘤的转基因 CAR 和 TCR 的临床相关临床前模型来确定膜束缚细胞因子对用于人类施用的工程化 T 细胞的影响。我们发现这些细胞因子通过 CAR 或 TCR T 自我传递-细胞通过重复刺激防止功能衰竭，并限制功能失调的自然杀伤 (NK) 样 T 细胞的出现。在不同的临床前鼠实体瘤模型中，我们观察到每种细胞因子的消退增强，但当 T 细胞同时包裹两种细胞因子时，抗肿瘤功效最大。膜束缚的 IL-15 和 IL-21 的共表达代表了一项技术增强工程化 T 细胞对抗实体瘤的弹性和功能，并可适用于多种治疗平台和疾病。

Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to universally improve patient outcomes. Here, we developed a technology to leverage the cooperative effects of IL-15 and IL-21, two common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T-cells and other lymphocytes, to enhance the efficacy of adoptive T-cells.We designed vectors that induce the constitutive expression of either membrane-tethered IL-15, IL-21, or IL-15/IL-21. We used clinically relevant preclinical models of transgenic CARs and TCRs against pediatric and adult solid tumors to determine the effect of the membrane-tethered cytokines on engineered T-cells for human administration.We found that self-delivery of these cytokines by CAR or TCR T-cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T-cells. Across different preclinical murine solid tumor models, we observed enhanced regression with each individual cytokine but the greatest anti-tumor efficacy when T-cells were armored with both.The co-expression of membrane-tethered IL-15 and IL-21 represents a technology to enhance the resilience and function of engineered T-cells against solid tumors and could be applicable to multiple therapy platforms and diseases.