Development of dipeptidyl peptidase inhibitors as novel immune adjuvants

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We have established that inhibition of DPPs prevents tumor development when initiated early after tumor injection in multiple models including pediatric sarcoma models. This effect is T cell and dendritic cell (DC) dependant and is associated with accelerated tumor-induced priming. We have determined that accelerated trafficking of DCs from the tumor environment to the draining lymph node is seen with DPP inhibition and that this effect requires the chemokines CCL19 and CCL21 and the associated receptor CCR7 suggesting that modulation of chemokine function may be involved. Finally, we have seen that administration of DPP inhibitor with tumor-targeted vaccines can mediate regression of large-established tumors suggesting that these molecules may be ideally suited as immune adjuvants. This work has been submitted for publication.In collaboration with Dr. Maria Tsokos in the laboratory of Pathology we have observed that the tumor microenvironment in pediatric sarcomas contains large numbers of monocytic cells (expressing CD63 and CD168). In a murine model of rhabdomyosarcoma we have seen a similar infiltration with myeloid cells that possess an immunosuppressive phenotype and sorted cells from these tumors can suppress T cell proliferation. Interestingly, when DPP inhibitors are administered these cells are phenotypically and functionally modulated to be less immunosuppressive suggesting that this effect may contribute to the adjuvant properties of these molecules. 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. Preclinical studies are ongoing in Dr. Hodge?s laboratory. In addition, based on the potent effects of these inhibitors in pediatric sarcoma models (described above) single agent studies in pediatric sarcomas are being considered in the Pediatric Oncology Branch.