The Vascular Disrupting Agent CA4P Improves the Antitumor Efficacy of CAR-T Cells in Preclinical Models of Solid Human Tumors
The Vascular Disrupting Agent CA4P Improves the Antitumor Efficacy of CAR-T Cells in Preclinical Models of Solid Human Tumors
复制标题
血管破坏剂 CA4P 提高 CAR-T 细胞在人类实体瘤临床前模型中的抗肿瘤功效
DOI：
10.1016/j.ymthe.2019.10.010
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发表时间：
2020-01-08
影响因子：
12.4
通讯作者：
Deng, Hongkui
中科院分区：
文献类型：
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作者：
Deng, Changwen;Zhao, Jingjing;Deng, Hongkui
由于CAR-T细胞的浸润和体内扩增不足，嵌合抗原受体（CAR）T细胞疗法对实体瘤仍然相对无效。与血液恶性肿瘤不同，实体瘤具有血管屏障，阻碍CAR-T细胞到达肿瘤部位。在这里，我们证明了考布他汀A-4磷酸盐（CA 4P），一种血管阻断剂（VDA），可以显著改善实体瘤中CAR-T细胞的浸润能力，这一点可以通过IFN-γ水平的升高来证明。此外，CA 4P和CAR-T细胞的联合治疗大大增加了CAR-T细胞在皮下卵巢癌小鼠异种移植模型和结肠癌和卵巢癌的患者来源的异种移植（PDX）模型中的治疗效率。我们的研究结果强调了CA 4P作为一种有效的抗肿瘤药物候选者，可与CAR-T细胞在临床应用中联合治疗实体瘤。
Chimeric antigen receptor (CAR) T cell therapy remains relatively ineffective against solid tumors due to inadequate infiltration and in vivo expansion of CAR-T cells. Unlike hematological malignancies, solid tumors have vascular barriers that hinder CAR-T cells from reaching the tumor site. Here, we demonstrated that combretastatin A-4 phosphate (CA4P), a vascular disrupting agent (VDA), can significantly improve the infiltration ability of CAR-T cells in solid tumors as evidenced by elevated levels of IFN-gamma. Moreover, combined treatment with CA4P and CAR-T cells greatly increased the therapeutic efficiency of the CAR-T cells in subcutaneous ovarian cancer mouse xenograft models and patient-derived xenograft (PDX) models of colon and ovarian carcinoma. Our findings highlight CA4P as an effective antitumor agent candidate for combination with CAR-T cells in clinical applications to treat solid tumors.