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，在多种模型中，肿瘤注射后早期启动时，对DPP的抑制会阻止肿瘤发育。有趣的是，这种回归发生在最初的肿瘤生长期之后，即使在峰值肿瘤大小下停止DPP抑制作用，也会观察到。使用耗竭实验和肿瘤补偿确定了T细胞的需求和选择性记忆的诱导。此外，我们已经证明了DPP抑制剂治疗不会增加肿瘤自然诱导的T细胞的大小，而是会加速肿瘤启动过程，从而导致肿瘤早期肿瘤反应性T细胞的增加。有趣的是，与未接受DPP抑制剂的肿瘤小鼠的T细胞相比，来自含有肿瘤的DPP抑制剂治疗的小鼠的T细胞会介导超肿瘤的上等抗肿瘤作用。值得注意的是，即使在收养转移后未施用其他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。使用抗原呈递细胞的选择性耗竭，我们已经证明，除了对DPP抑制剂介导的肿瘤消退的T细胞需求外，还需要树突状细胞。与通过肿瘤加速的T细胞启动一致，DPP抑制剂治疗导致DC加速对肿瘤排出淋巴结的运输。正在进行的研究集中在加速直流运输的机制上。重要的是，针对直流运输是一种基于免疫学的癌症治疗的新方法。最后，尽管在肿瘤攻击后后来对DPP抑制剂治疗的启动并不能阻止肿瘤的生长，但DPP抑制剂与靶向肿瘤的DC疫苗接种的组合导致多个肿瘤模型中大型已建立的肿瘤的消退。 与Bill Bachovchin博士合作，我们现在正在测试多个DPP抑制剂，其在我们的肿瘤疫苗模型中选择性靶向不同的DPP酶，并计划选择最佳抑制剂以及在癌症患者中潜在的未来临床试验的最佳平台。