Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15
Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15
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DOI：
10.1158/1078-0432.ccr-18-1811
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发表时间：
2019-05-01
影响因子：
11.5
通讯作者：
Savoldo, Barbara
中科院分区：
文献类型：
--
作者：
Chen, Yuhui;Sun, Chuang;Savoldo, Barbara
目的：在循环中遇到同源抗原的延迟以及在肿瘤部位接受的次优共刺激是嵌合抗原受体重定向T细胞（CAR-T）在实体瘤中活性有限的关键原因。我们已经探索了将IL 15细胞因子掺入CAR盒中以提供抗原遭遇前的存活信号和使用神经母细胞瘤肿瘤模型在肿瘤部位处的额外细胞因子信号传导的益处。CAR）或IL 15（GD 2.车15）。然后，我们比较了扩展，表型，和抗肿瘤活性的T细胞转导这些结构对一系列的神经母细胞瘤细胞系在体外和体内使用异种转移模型neuroblastoma.Results：我们观察到，优化GD 2。车与GD 2相比，15-Ts具有降低的PD-1受体表达，富含干细胞样细胞，并且在体外和体内重复肿瘤暴露时具有上级抗肿瘤活性。CAR-Ts。体内肿瘤再激发实验进一步强调了IL 15在外周血和组织中促进增强的CAR-T抗肿瘤活性和存活的作用。最后，包含诱导型胱天蛋白酶-9基因（iC 9）安全开关保证了工程化GD 2的有效按需消除。车15-Ts.结论：我们的研究结果指导GD 2的新治疗选择。CAR-T在神经母细胞瘤患者中的应用，以及CAR-T在广泛的实体瘤中的发展。
Purpose: A delay in encountering the cognate antigen while in the circulation, and the suboptimal costimulation received at the tumor site are key reasons for the limited activity of chimeric antigen receptor-redirected T cells (CAR-T) in solid tumors. We have explored the benefits of incorporating the IL15 cytokine within the CAR cassette to provide both a survival signal before antigen encounter, and an additional cytokine signaling at the tumor site using a neuroblastoma tumor model.Experimental Design: We optimized the construct for the CAR specific for the NB-antigen GD2 without (GD2. CAR) or with IL15(GD2. CAR. 15). We then compared the expansion, phenotype, and antitumor activity of T cells transduced with these constructs against an array of neuroblastoma cell lines in vitro and in vivo using a xenogeneic metastatic model of neuroblastoma.Results: We observed that optimized GD2. CAR. 15-Ts have reduced expression of the PD-1 receptor, are enriched in stem cell-like cells, and have superior antitumor activity upon repetitive tumor exposures in vitro and in vivo as compared with GD2. CAR-Ts. Tumor rechallenge experiments in vivo further highlighted the role of IL15 in promoting enhanced CAR-T antitumor activity and survival, both in the peripheral blood and tissues. Finally, the inclusion of the inducible caspase-9 gene (iC9) safety switch warranted effective on demand elimination of the engineered GD2. CAR. 15-Ts.Conclusions: Our results guide new therapeutic options for GD2. CAR-Ts in patients with neuroblastoma, and CAR-T development for a broad range of solid tumors.