肿瘤细胞治疗研究
英文原题：Specific loading of oncolytic VSV on CAR enhances CAR-T cell signaling and antitumor activity.
溶瘤病毒（OVs）已被证明可提高嵌合抗原受体（CAR）T 细胞治疗实体瘤的疗效。
研究显示，溶瘤病毒（OV）可增强嵌合抗原受体（CAR）T细胞治疗实体瘤的疗效。然而，由于两种药物在肿瘤组织中分布不均，以及病毒感染导致CAR-T细胞耗竭，其联合效果有限。在此，我们通过将低密度脂蛋白受体的CR2和CR3结构域插入CAR结构，设计了一种CAR构件（CR2/3-CAR）。低密度脂蛋白受体是溶瘤水疱性口炎病毒（VSV）突变株VSVΔ51的病毒受体，因此该设计可使VSVΔ51特异性装载至CAR-T细胞。锚定的VSVΔ51可从CAR-T细胞释放，并高效递送至肿瘤组织。进一步研究发现，病毒包膜蛋白与CR2/3-CAR结构之间的交联促进了无抗原CAR簇及抗原诱导CAR免疫突触形成，触发CAR信号传导，并直接预先活化CAR-T细胞。因此，该方法显著增强CAR-T细胞增殖、代谢适应力及免疫活性，进而增强OV/CAR-T协同细胞毒作用，为实体瘤治疗提供了有效策略。
Oncolytic viruses (OVs) have been shown to increase the efficacy of chimeric antigen receptor (CAR) T cells in treating solid tumors. However, their combined effect has been limited by the unbalanced distribution of two agents in tumor tissue and viral infection-mediated CAR-T cell exhaustion. Here, we designed a CAR moiety by inserting the CR2 and CR3 domains (CR2/3-CAR) of low-density lipoprotein receptor, which is the viral receptor of oncolytic vesicular stomatitis virus (VSV) mutant (VSV 51), enabling specific loading of VSV 51 onto CAR-T cells. The anchored VSV 51 could be released from CAR-T cells and efficiently delivered to tumor tissue. Further investigation revealed that the cross-connection between viral envelope proteins and CR2/3-CAR moieties facilitated forming antigen-free CAR clusters and antigen-induced CAR synapse, triggered CAR signaling transduction, and directly pre-activated the CAR-T cells. Consequently, this approach potently enhanced the proliferation, metabolic fitness, and immunological activities of CAR-T cells, and subsequently enhanced the OV/CAR-T synergetic cytotoxicity, revealing an effective strategy for treating solid tumors.
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