Development of dipeptidyl peptidase inhibitors as novel immune adjuvants

二肽基肽酶抑制剂作为新型免疫佐剂的开发

• 批准号: 8157750
• 负责人: Terry Fry
• 金额: $ 13.2万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157750
• 关键词: Dendritic Cells; Development; Dipeptidyl Peptidases; Immunologic Adjuvants; Non-Insulin-Dependent Diabetes Mellitus; Protease Inhibitor; glucagon-like peptide; novel

We have established that inhibition of DPPs prevent tumor development when initiated early after tumor injection in multiple models. Interestingly, this regression occurs after an initial period of tumor growth and is observed even when DPP inhibition is stopped at peak tumor size. The requirement for T cells and the induction of selective memory has been established using depletion experiments and tumor rechallenge. In addition, we have demonstrated that DPP inhibitor treatment does not increase the magnitude of the T cells naturally induced by tumors, but rather accelerates the process of tumor priming resulting in increased tumor-reactive T cells early during tumor growth. Interestingly, T cells from tumor-bearing DPP inhibitor treated mice mediate superior anti-tumor effects upon adoptive transfer into lymphopenic mice when compared to T cells from tumor bearing mice not receiving DPP inhibitor. Remarkably, this enhanced T cell functionality is observed even when no additional DPP inhibitor is administered following adoptive transfer. Ongoing experiments are exploring the basis for enhanced T cell function. Using selective depletion of antigen presenting cells we have demonstrated that, in addition to the T cell requirement for DPP inhibitor-mediated tumor regression, dendritic cells are also required. Consistent with the accelerated T cell priming by tumor, DPP inhibitor treatment results in accelerated trafficking of DCs to tumor draining lymph nodes. Ongoing studies are focused on the mechanism for accelerated DC trafficking. Importantly, targeting DC trafficking represents a novel approach for immunologically-based cancer therapy. Finally, although initiation of DPP inhibitor treatment later following tumor challenge did not prevent tumor growth, combination of DPP inhibitor with tumor-targeted DC vaccination resulted in regression of large established tumors in multiple tumor models. In collaboration with Dr. Bill Bachovchin, we are now testing multiple DPP inhibitors with selective targeting of different DPP enzymes in our tumor vaccine models with plans to choose the optimal inhibitor as well as the optimal platform for potential future clinical trials in patients with cancer.

我们已经确定，在多个模型中，在肿瘤注射后早期开始抑制 DPP 可以预防肿瘤的发展。有趣的是，这种消退发生在肿瘤生长的初始阶段之后，即使在肿瘤大小达到峰值时停止 DPP 抑制也能观察到这种消退。通过耗竭实验和肿瘤再攻击已经确定了对 T 细胞的需求和选择性记忆的诱导。此外，我们已经证明，DPP 抑制剂治疗不会增加肿瘤自然诱导的 T 细胞的数量，而是加速肿瘤启动过程，导致肿瘤生长早期肿瘤反应性 T 细胞增加。有趣的是，与未接受 DPP 抑制剂治疗的荷瘤小鼠的 T 细胞相比，经 DPP 抑制剂治疗的荷瘤小鼠的 T 细胞在过继转移至淋巴细胞减少的小鼠中后介导了更好的抗肿瘤作用。值得注意的是，即使在过继转移后没有施用额外的 DPP 抑制剂，也可以观察到这种增强的 T 细胞功能。正在进行的实验正在探索增强 T 细胞功能的基础。通过选择性清除抗原呈递细胞，我们已经证明，除了 DPP 抑制剂介导的肿瘤消退需要 T 细胞外，还需要树突状细胞。与肿瘤加速 T 细胞启动一致，DPP 抑制剂治疗导致 DC 加速运输至肿瘤引流淋巴结。正在进行的研究重点是加速 DC 贩运的机制。重要的是，靶向 DC 运输代表了一种基于免疫学的癌症治疗的新方法。最后，尽管肿瘤攻击后稍后开始 DPP 抑制剂治疗并不能阻止肿瘤生长，但 DPP 抑制剂与肿瘤靶向 DC 疫苗接种的组合导致多种肿瘤模型中已形成的大型肿瘤消退。 我们与 Bill Bachovchin 博士合作，目前正在肿瘤疫苗模型中测试多种 DPP 抑制剂，选择性靶向不同的 DPP 酶，并计划选择最佳抑制剂以及未来潜在的癌症患者临床试验的最佳平台。