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. Although DPP inhibitor treatment increases the number of IL-17-producing T cells, a population known to posses potent anti-tumor activity, tumor regression remained intact in mice lack IL-17 or IL-23p19 (obtained from Dr. Giorgio Trinchieri), a cytokine also important in IL-17 producing TC ell 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. Anti-tumor activity is lost in plt/plt mice lacking the chemokines responsible DC trafficking to tumor draining lymph node, CCL19 and CCL21. In addition, preliminary data demonstrates increased secretion of CCL19 by lymph nodes exposed to DPP inhibitors. Ongoing studies are confirming these results using mice deficient in the receptor for CCL19/21 on DCs, CCR7. Finally, although initiation of DPP inhibitor treatment later following tumor challenge does not prevent tumor growth, combination of DPP inhibitor with tumor-targeted DC vaccination results in regression of large established tumors in multiple tumor models including a model of pediatric sarcoma. Thus, our studies demonstrate that DPP inhibitors represent potent vaccine adjuvants with novel mechanism of action that targets DCs and would be predicted act synergistically with agents directly targeting tumor-specific T cells such as cytokines. 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. We have identified a second-generation compound with improved therapeutic window in mice and increased adjuvant activity. We have begun to discuss a early phase clinical development plan for this agent with Dr. Jeff Schlom, Dr. James Gulley and Dr. Jim Hodge in the Laboratory of Tumor Immunology and Biology in adult malignancies. Depending on the outcome of these studies, subsequent trials will be considered in the Pediatric Oncology Branch using vaccine platforms already being tested in humans (solid tumor vaccines in collaboration with Dr. Crystal Mackall and hematologic malignancies through the Blood and Marrow Transplant Section (see Project ZIA BC 011295) and in collaboration with Dr. Alan Wayne).
|Duncan, Brynn B; Highfill, Steven L; Qin, Haiying et al. (2013) A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy. J Immunother 36:400-11|
|Dromi, Sergio A; Walsh, Meghaan P; Herby, Sarah et al. (2009) Radiofrequency ablation induces antigen-presenting cell infiltration and amplification of weak tumor-induced immunity. Radiology 251:58-66|