Development of dipeptidyl peptidase inhibitors as novel immune adjuvants

点击翻译按钮获取中文摘要

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.