CAR - T细胞包装的溶瘤痘苗病毒显示增强的抗肿瘤效果

Kevin Song, Xing-bing Wang
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摘要

背景:溶瘤痘苗病毒是一种很有前途的癌症治疗方式。然而,溶瘤病毒的有效性受到几个因素的限制。牛痘病毒的全身或肿瘤内递送,以及随后由病毒诱导的强大免疫反应将病毒从肿瘤部位和体内迅速清除,是主要挑战之一。在这项研究中,我们探索了CAR - T细胞包装的溶瘤痘苗病毒作为一种联合治疗策略,以克服目前溶瘤病毒治疗的局限性。材料和方法:制备人HER2-CAR T细胞,用EphA2-CD3 T细胞接合剂溶瘤痘苗病毒感染HER2-CAR T细胞,并通过流式分析和病毒滴度分析评估病毒在T细胞内的感染性和复制性。ELISA法和51Cr释放法检测T细胞活化和细胞毒性。结果:我们证实溶瘤痘苗病毒能有效感染人HER2-CAR T细胞,并且在3天内激活的人T细胞中的病毒颗粒增加了1000倍以上。此外,在HER2dimEphA2high的NSCLC A549细胞系存在时,EphA2-CD3 T细胞参与器可以有效激活HER2-CAR - T细胞,这可以通过IFNγ和IL2的表达水平升高来证明。重要的是,体外研究表明,与HER2-CAR -T细胞或单独使用EphA2-TEA-VV相比,HER2-CAR -T细胞包装的EphA2-TEA-VV对HER2dimEphA2high的NSCLC A549细胞系表现出更强的细胞毒性。结论:HER2-CAR -T细胞包装的EphA2-TEA-VV能够克服病毒的高免疫原性和肿瘤异质性,从而增强抗肿瘤作用,是一种很有前景的治疗候选药物。
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CAR T Cell-Packaged Oncolytic Vaccinia Virus Displays Enhanced Antitumor Efficacy
Background: Oncolytic vaccinia virus is a promising cancer therapeutic modality. However, the effectiveness of oncolytic viruses is limited by several factors. Systemic or intratumoral delivery of vaccinia viruses with the subsequent quick clearance of the viruses from the tumor site and the body by the strong immune responses induced by the virus are among the key challenges. In this study, we explored CAR T cell-packaged oncolytic vaccinia virus as a combinational therapy strategy in order to overcome current limitations for oncolytic virotherapy. Materials and Methods: We generated human HER2-CAR T cells and infected the HER2-CAR T cells with a EphA2-CD3 T cell engager-armed oncolytic vaccinia virus and evaluated the virus infectivity and replication within the T cells by flow analysis and virus tittering. T cell activation and cytotoxicity were determined by ELISA and 51Cr release assay. Results: We demonstrated that oncolytic vaccinia virus infected human HER2-CAR T cells effectively and virus particle in the activated human T cells increased >1000 fold in 3 days. In addition, EphA2-CD3 T cell engager effectively activated HER2-CAR T cells in the presence of HER2dimEphA2high NSCLC A549 cell lines, indicated by the elevated expression level of IFNγ and IL2. Importantly, in vitro studies showed that HER2-CAR T cell-packaged EphA2-TEA-VV displayed enhanced cytotoxicity against HER2dimEphA2high NSCLC A549 cell lines compared to HER2-CAR T cells or EphA2-TEA-VV alone. Conclusion: HER2-CAR T cell-packaged EphA2-TEA-VV is a promising therapeutic candidate with the ability to overcome the virus’s high immunogenicity and tumor heterogeneity, resulting in enhanced antitumor effects.
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