Data Sheet 1_Enhanced anti−tumor efficacy of “IL−15 and CCL19” −secreting CAR−T cells in human glioblastoma orthotopic xenograft model.pdf

Despite the remarkable success of CAR-T cell therapy in hematologic malignancies, its progress in solid tumors has been slow. Overcoming challenges such as the recruitment and infiltration of CAR-T cells into the tumor site and the survival issues in the harsh tumor microenvironment are crucial for successful application in solid tumors. In this study, CAR-T cells were engineered to secrete both IL-15 and CCL19, and their efficacy was evaluated in a human glioblastoma orthotopic xenograft model. The results reveal that 15 × 19 CAR-T cells exhibit superior proliferation, chemotaxis, and phenotypic characteristics compared to conventional CAR-T cells in vitro. In vivo, 15 × 19 CAR-T cells exhibit superior control over tumors compared to conventional counterparts. Mechanistically, the improved efficacy can be attributed, in part, to IL-15 and CCL19 enhancing T-cell infiltration at the tumor site and fortifying resistance to exhaustion within the tumor microenvironment. In conclusion, the incorporation of IL-15 and CCL19 into CAR-T cells emerges as a promising strategy to elevate the anti-tumor efficacy of CAR-T cell therapy, positioning 15 × 19 CAR-T cells as a potential breakthrough for enhancing the application of CAR-T therapy in solid tumors.

尽管嵌合抗原受体T细胞（CAR-T）疗法在血液系统恶性肿瘤中已取得显著成效，但其在实体瘤领域的进展却相对迟缓。克服CAR-T细胞招募并浸润至肿瘤部位、以及在恶劣肿瘤微环境中存活等诸多挑战，是实现其在实体瘤中成功应用的核心关键。本研究通过基因工程改造CAR-T细胞，使其同时分泌IL-15与CCL19，并在人脑胶质母细胞瘤原位异种移植模型中评估其抗肿瘤功效。体外实验结果显示，15×19 CAR-T细胞相较于传统CAR-T细胞，展现出更优异的增殖能力、趋化活性与表型特征。体内实验则表明，15×19 CAR-T细胞对肿瘤的控制效果显著优于传统CAR-T细胞。从机制层面分析，疗效提升可部分归因于IL-15与CCL19能够增强T细胞在肿瘤部位的浸润，并强化其在肿瘤微环境中的抗耗竭能力。综上，在CAR-T细胞中整合IL-15与CCL19，有望成为提升CAR-T疗法抗肿瘤效能的极具前景的策略，使15×19 CAR-T细胞成为增强CAR-T疗法在实体瘤中应用潜力的潜在突破方向。