抗原修饰联合NO递送增强NY-ESO-1TCR-T特异性抗肿瘤作用的研究

申请人团队成功建立了iRGD修饰联合PD-1基因敲除的NY-ESO-1TCR-T细胞制备技术。然而，该项技术实际应用时可能面临肿瘤细胞特异性抗原表达缺失导致TCR-T无法激活和肿瘤血管异常导致TCR-T被阻隔在肿瘤外区域的瓶颈。基于文献调研及前期工作基础，我们推测：将特异性抗原及肿瘤微环境调节剂通过纳米载体递送给肿瘤，可解决上述难题。本项目拟制备偶联肿瘤抗原和iRGD并负载NO供体的纳米脂质体，当其特异性进入肿瘤组织，靶抗原NY-ESO-1融合到肿瘤细胞膜上，同时NO被缓慢释放，肿瘤的血管灌注与缺氧状态改善，肿瘤相关巨噬细胞由M2型向M1型转化，此时回输iRGD-PD-1-KO-NY-ESO-1TCR-T，可显著提高TCR-T疗效。通过体内外模型，研究此新型生物活性载体协同TCR-T抗肿瘤效果及其机制，预期结果有望建立一种“通用型”细胞治疗新技术，为其临床应用提供理论和实验依据。

Our team successfully established iRGD inserted and PD-1 gene knockout TCR-T preparation technology for NY-ESO-1. However, this technique is facing two major bottlenecks in the clinical treatment. On one hand, the lack of tumor-specific antigen expression leads to the inactivation of TCR-T cells; on the other hand, TCR-T cells are blocked in the external tumor area due to abnormal tumor vessels. Based on literature research and our preliminary work, we propose that these problems can be addressed through delivering specific antigens and TME regulators to tumor area. Therefore, this research will aim at constructing DSPE-PEG nano-liposomes which are coaggregated with NY-ESO-1 epitope、iRGD and loaded with NO donor DNIC. When nano-liposomes target into tumor area through both active and passive ways, NY-ESO-1 epitope can be fused to tumor cell membrane, and NO can be slowly released. Thus blood perfusion and anoxic conditions can be improved, TAM can be converted from M2 to M1 type, resulting in synergic anti-tumor effect with PD-1-KO-NY-ESO-1TCR-T. We will use in vivo and in vitro models to study the anti-tumor effect and underlying mechanisms of the new targeted bioactive-delivery system co-interaction with TCR-T. The results are expected to present a new universal cellular immunotherapy technology, providing theoretical and experimental basis for its potential clinical applications.