A NANOPARTICLE CD8 T CELL REGIMEN FOR CANCER THERAPY

尽管在过去几十年中取得了很大进展，但目前的肿瘤免疫治疗方法仍然不如预期的成功。阻止有效抗肿瘤免疫发展的一个主要障碍是大多数肿瘤细胞缺乏T细胞活化所必需的共刺激信号，并且受到抑制性细胞因子如TGF-β的保护。最近我们和其他人的研究发现，CD 8 + T细胞消融的Cbl-b，泛素E3连接酶家族的成员，可能会克服这种障碍，从而提供一个新的靶点，引发针对广谱癌症的有效抗肿瘤免疫。在这项提案中，我们提出了一个计划，以产生一种修饰版本的纳米颗粒，以特异性沉默小鼠和人类CD 8 + T细胞中的Cbl-b。这种与单链CD 8抗体缀合的纳米颗粒系统预期将siRNA特异性递送至CD 8 + T细胞并促进siRNA释放至胞质溶胶中。我们建议使用改进的纳米颗粒来确定这种靶向siRNA递送系统是否可以沉默野生型小鼠或用人PBMC重建的hu-SCID小鼠中的小鼠或人CD 8 + T细胞中的Cbl-b。我们希望这种载体的可用性将为下一阶段的研究奠定坚实的基础，以使用小鼠肿瘤模型和人类临床试验来测试基于多功能纳米颗粒的癌症治疗策略。

Despite much progress that has been made during past decades, current approaches in tumor immunotherapy remain less successful than desired. One major obstacle that prevents development of effective anti-tumor immunity is that most tumor cells lack the co-stimulatory signals essential for T cell activation and are protected by the suppressive cytokines such as TGF-beta. Recent studies by us and others have identified that CD8+ T cells ablated Cbl-b, a member of ubiquitin E3 ligase family, may overcome such an obstacle and thus provide a novel target for eliciting effective anti-tumor immunity against a broad spectrum of cancers. In this proposal, we present a plan to generate a modified version of nanoparticle to specifically silence Cbl-b in mouse and human CD8+ T cells. This nanoparticle system conjugated with single chain CD8 antibody is anticipated to deliver siRNA specifically to CD8+ T cells and facilitate siRNA release into the cytosol. We propose to use the improved nanoparticles to determine whether this targeted siRNA delivery system can silence Cbl-b in mouse or human CD8+ T cells in wild type mice or hu-SCID mice reconstituted with human PBMCs. We expect that availability of such vehicles will set up a solid foundation to proceed to next stage of study to test the multifunctional nanoparticle-based strategy in cancer therapy using mouse tumor models and in human clinical trials.