Development of dipeptidyl peptidase inhibitors as novel immune adjuvants

我们已经在多个模型中证实，在肿瘤注射后早期开始抑制DPPs可以防止肿瘤的发展。有趣的是，这种回归发生在肿瘤生长的初始阶段，即使在肿瘤大小达到峰值时DPP抑制停止，也能观察到。对T细胞的需求和选择性记忆的诱导已经通过消耗实验和肿瘤再挑战建立。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细胞的大小，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，接受DPP抑制剂治疗的小鼠的T细胞在过继转移到淋巴细胞减少小鼠时介导了更强的抗肿瘤作用。值得注意的是，即使在过继转移后没有使用额外的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。通过选择性消耗抗原呈递细胞，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，树突状细胞也是必需的。与肿瘤加速T细胞启动一致，DPP抑制剂治疗导致dc加速运输到肿瘤引流淋巴结。正在进行的研究的重点是加速DC贩运的机制。重要的是，靶向DC贩运代表了一种基于免疫的癌症治疗的新方法。最后，尽管在肿瘤攻击后开始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疫苗联合使用可在多种肿瘤模型中导致大肿瘤的消退。与Bill Bachovchin博士合作，我们现在正在肿瘤疫苗模型中测试多种选择性靶向不同DPP酶的DPP抑制剂，并计划选择最佳抑制剂以及用于癌症患者潜在的未来临床试验的最佳平台。

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.