Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts
Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts
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DOI：
10.1016/j.omto.2020.04.013
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发表时间：
2020-06-26
影响因子：
5.7
通讯作者：
Wang, Shu
中科院分区：
文献类型：
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作者：
Ang, Wei Xia;Ng, Yu Yang;Wang, Shu
基于V-Gamma、9V-Delta2T细胞的抗癌免疫治疗在早期临床试验中显示出一些希望，但仍有很大的改进空间。利用人NKG2D的胞外区，我们构建了NKG2D配体特异性嵌合抗原受体(CARS)。我们采用了一种非病毒的CAR方法，通过mRNA电穿孔来修饰V-Gamma 9V Delta 2T细胞，并证明了在与NKG2D配体阳性的癌细胞相互作用后，CARS显著增强了修饰后的细胞对多种培养的实体瘤细胞的杀伤活性，包括那些对Zometa治疗耐药的细胞。在已建立肿瘤的小鼠中，重复剂量的CAR表达细胞导致肿瘤消退，与PBS对照组相比，中位生存期延长了132%。这一发现表明，RNA CAR修饰的V-Gamma 9V Delta 2T细胞具有治疗多种NKG2D配体表达的癌症的临床潜力。
V gamma 9V delta 2 T cell-based anticancer immunotherapy has shown some promise in early-phase clinical trials but there is still large room for improvement. Using the extracellular domain of the human NKG2D, a stimulatory receptor expressed by V gamma 9V delta 2 T cells, we constructed NKG2D ligand-specific chimeric antigen receptors (CARs). We adopted a non-viral CAR approach via mRNA electroporation to modify V gamma 9V delta 2 T cells and demonstrated that, upon interaction with the NKG2D ligand-positive cancer cells, the CARs substantially enhanced the cytotoxic activity of the modified cells toward multiple cultured solid tumor cell lines, including those resistant to Zometa treatment. Repeated doses of the CAR-expressing cells resulted in tumor regression in mice with established tumors, extending median survival time by up to 132% as compared to the PBS control group. The findings suggest clinical potential for RNA CAR-modified V gamma 9V delta 2 T cells to treat a wide variety of NKG2D ligand-expressing cancers.