A NANOPARTICLE CD8 T CELL REGIMEN FOR CANCER THERAPY

用于癌症治疗的纳米颗粒 CD8 T 细胞方案

• 批准号: 7950393
• 负责人: JIAN LI
• 金额: $ 19.81万
• 依托单位: NANOTARGET, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950393
• 关键词: NANOPARTICLE; CD8; CELL; REGIMEN; CANCER

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.

尽管在过去的几十年里取得了很大的进展，但目前的肿瘤免疫治疗方法仍然不如预期的成功。阻碍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细胞激活所必需的共刺激信号，并受到tgf - β等抑制性细胞因子的保护。我们和其他人最近的研究已经发现，CD8+ T细胞消融Cbl-b（泛素E3连接酶家族的成员）可能克服这一障碍，从而为激发针对广泛癌症的有效抗肿瘤免疫提供了新的靶点。在这项提议中，我们提出了一项计划，以产生一种修饰版的纳米颗粒来特异性地沉默小鼠和人类CD8+ T细胞中的Cbl-b。这种结合单链CD8抗体的纳米颗粒系统有望将siRNA特异性地递送到CD8+ T细胞，并促进siRNA释放到细胞质中。我们建议使用改进的纳米颗粒来确定这种靶向siRNA递送系统是否可以在野生型小鼠或用人PBMCs重组的hu-SCID小鼠中沉默小鼠或人CD8+ T细胞中的Cbl-b。我们期望这种载体的可用性将为进行下一阶段的研究奠定坚实的基础，以测试基于多功能纳米颗粒的癌症治疗策略，使用小鼠肿瘤模型和人体临床试验。