Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion
Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion
复制标题
IL7 和 CCL21 的共表达可提高 CAR-T 细胞在实体瘤中的功效，无需预条件淋巴细胞清除
DOI：
10.1158/1078-0432.ccr-20-0777
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发表时间：
2020-10-15
影响因子：
11.5
通讯作者：
Li, Zonghai
中科院分区：
文献类型：
--
作者：
Luo, Hong;Su, Jingwen;Li, Zonghai
目的T细胞的募集、存活和增殖是嵌合抗原受体（CAR）T细胞治疗实体瘤的重要限制因素。在这项研究中，我们将CAR-T细胞改造为共表达细胞因子IL 7和CCL 21（7 × 21 CAR-T），这是一种细胞因子组合，旨在提高CAR-T细胞的增殖和趋化性。实验设计使用逆转录病毒载体转导制备共表达细胞因子的CLDN 18. 2特异性第二代CAR-T细胞。在体外评价基因工程CAR-T细胞的增殖和迁移。结果7 × 21的CAR-T细胞在体外的增殖能力和趋化能力均明显高于常规CAR-T细胞，在体内的增殖能力和趋化能力明显高于常规CAR-T细胞，在体内的趋化能力明显高于常规CAR-T细胞，在体内的趋化能力明显高于常规CAR-T细胞。7 × 21个CAR-T细胞显示出优于常规CAR-T细胞或7 × 19个CAR-T细胞的上级治疗效果。如先前在三种不同的实体瘤中报道的，在没有环磷酰胺预处理的情况下共表达IL 7和CCL 19的T细胞。有趣的是，7 × 21个CAR-T细胞也可以通过异质性抗原表达抑制肿瘤生长，甚至诱导肿瘤完全缓解。在机制上，IL 7和CCL 21显著改善了肿瘤中CAR-T细胞和树突状细胞的存活和浸润。结论IL 7和CCL 21共表达可增强CAR-T细胞的抗肿瘤活性，7 × 21的CAR-T细胞有望成为治疗实体瘤的新策略。
PurposeT-cell recruitment, survival, and proliferation are the important limitations to chimeric antigen receptor (CAR) T cells therapy in the treatment of solid tumors. In this study, we engineered CAR-T cells to coexpress cytokines IL7 and CCL21 (7 × 21 CAR-T), a cytokine combination in order to improve proliferation and chemotaxis of CAR-T cells.Experimental DesignCLDN18.2-specific second-generation CAR-T cells coexpressing cytokines were prepared using retroviral vector transduction. The proliferation and migration of genetically engineered CAR-T cells were evaluatedin vitro. The antitumor activities of genetically engineered CAR-T cells were evaluated against multiple solid tumors in C57BL/6 micein vivo.ResultsIn vitro, the proliferation and chemotaxis of 7 × 21 CAR-T cells are significantly improved when compared with those of the conventional CAR-T cells.In vivo, 7 × 21 CAR-T cells revealed superior therapeutic effects to either conventional CAR-T cells or 7 × 19 CAR-T cells which coexpress IL7 and CCL19 as previously reported in three different solid tumors without cyclophosphamide precondition. Interestingly, 7 × 21 CAR-T cells could also suppress the tumor growth with heterogeneous antigen expression and even induce tumor complete remission. Mechanistically, IL7 and CCL21 significantly improved survival and infiltration of CAR-T cells and dendritic cells in tumor. In addition, CCL21 also inhibited the tumor angiogenesis as proved by IHC.ConclusionsCoexpression of IL7 and CCL21 could boost CAR-T cells' antitumor activity, and 7 × 21 CAR-T cells may be served as a promising therapy strategy for solid tumors.