PD-1纳米抗体增强肿瘤特异性CTL抗癌效应及机制研究

在过继T细胞治疗肿瘤研究领域，怎样提高肿瘤抗原特异性CTL抗肿瘤效果是需要解决的关键科学问题。基于本课题组前期筛选出的PD-1纳米抗体PD-1Nb20，结合本课题组建立的高效DC/肿瘤融合细胞诱导特异性CTL技术，本项目首先拟研究PD-1Nb20抗肿瘤效应和相关机制；然后体外研究PD-1Nb20增强DC/肿瘤融合细胞诱导的CTL生物学活性；进一步采用PD-1Nb20增强DC/肿瘤融合细胞诱导的CTL过继治疗荷癌NOD/SCID鼠，体内探索其抗癌效应及机制。本项目设计采用PD-1纳米抗体阻断T细胞活化过程这一重要的负性信号分子，防止PD-1对T细胞活化后的抑制作用，使增强CTL抗肿瘤效应成为可能的新策略。通过本项目研究，不仅为研制理想抗肿瘤抗体药物提供新的手段，而且为提高CTL数量和活性提供新的方法学和理论指导，将为抗体药物研究领域和肿瘤过继治疗带来新的突破。

In research fields of adoptive T-cell therapy for tumors, enhancing the antitumor efficacy of tumor specific cytotoxic T lymphocytes remains a formidable challenge. Based on our previously developed novel anti-PD-1 nanobody PD-1Nb20, and our invented technology of generating highly-efficient DC/tumor hybrid-induced CTLs, we plan to explore: 1) Preparation of the PD-1Nb20 and the antitumor efficacy of the PD-1Nb20 and the corresponding mechanism. 2) The ability of PD-1Nb20 to potentiate the bioactivities of DC/tumor hybrid-induced CTLs in vitro. 3) Exploration of the antitumor efficacy and mechanism of tumor specific CTLs enhanced by PD-1Nb20 in vivo. This project design is based on using anti-PD-1 nanobody to systematically block PD-1 function, a key negative regulator of T-cell activation. Overcoming of PD-1 mediated inhibition on T-cell activation will potentiate the antitumor efficacy for CTLs. This project will not only exploit innovative strategies toward designing ideal antitumor drugs, but also provide a new methodological and theoretical guidance to improve the quantity and activity for DC/tumor hybrid-induced CTLs. This project also provides a fantastic opportunity to bring new breakthrough in antibody-drug research fields and tumor adoptive therapy.