肿瘤细胞治疗研究
英文原题：Armored Chimeric Antigen Receptor T-cell Therapy Targets Antigen-Heterogeneous Glioma.
未标注：嵌合抗原受体（CAR）T 细胞疗法在缺乏有效治疗选择的胶质母细胞瘤中显示出早期前景。
未标注：嵌合抗原受体（CAR）T 细胞疗法在缺乏有效治疗选择的胶质母细胞瘤中显示出早期希望，但两项主要挑战限制其疗效：肿瘤抗原异质性和免疫抑制性肿瘤微环境。经工程化改造、可分泌多种免疫调节蛋白的 CAR-T 细胞能够逆转免疫抑制并募集内源性免疫。通过对潜在协同装甲组合进行体内头对头比较，研究证实，在免疫功能完整小鼠中，同时表达 CAR、IL-12 和抗诱饵型 IL-18（DR18）的 T 细胞（CAR-12.DR18）对抗原异质性胶质瘤具有强效疗效。将 CAR-12.DR18 T 细胞与分泌抗血管内皮生长因子（抗 VEGF）单链可变片段（scFv）的 CAR-T 联合给药，可在有效缓解毒性的同时实现强效抗肿瘤疗效。这种联合疗法提供了一种具有临床应用潜力的策略，以克服胶质母细胞瘤有效治疗的关键障碍。 意义：装甲化细胞因子并分泌抗 VEGF 单链可变片段的 CAR-T 细胞，可在毒性极低的情况下控制原位、抗原异质性胶质瘤，为迫切需要有效治疗的胶质母细胞瘤患者提供治疗策略。
UNLABELLED: Chimeric antigen receptor (CAR) T-cell therapy has shown early promise against glioblastoma, which lacks effective treatment options. However, two key challenges curtail efficacy: tumor-antigen heterogeneity and an immunosuppressive tumor microenvironment. CAR T cells engineered to secrete combinations of immunomodulatory proteins can reverse immune suppression and engage endogenous immunity. Through head-to-head in vivo comparisons of potentially synergistic armor combinations, we demonstrated that T cells expressing a CAR plus IL12 and the decoy-resistant form of IL18 (CAR-12.DR18 T cells) show strong efficacy against antigen-heterogeneous glioma in immunocompetent mice. Robust antitumor efficacy with effective toxicity mitigation was achieved via combined administration of CAR-12.DR18 T cells with CAR T cells that secrete an anti-vascular endothelial growth factor (anti-VEGF) single-chain variable fragment (scFv). This combination therapy presents a clinically applicable strategy to overcome key barriers to the effective treatment of glioblastoma. SIGNIFICANCE: CAR-T cells armored with cytokines and anti-VEGF single-chain variable fragments can control orthotopic, antigen-heterogeneous glioma with minimal toxicity, providing a therapeutic strategy for glioblastoma patients in urgent need of efficacious treatments.
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