Development of dipeptidyl peptidase inhibitors as novel immune adjuvants

我们已经在包括儿童肉瘤模型在内的多种模型中证实，在肿瘤注射后早期开始抑制DPPs可以防止肿瘤的发展。这种效应依赖于T细胞和树突状细胞（DC），并与肿瘤诱导的加速启动有关。我们已经确定，DPP抑制可以加速dc从肿瘤环境到引流淋巴结的运输，这种作用需要趋化因子CCL19和CCL21以及相关受体CCR7，这表明可能参与了趋化因子功能的调节。最后，我们已经看到DPP抑制剂与肿瘤靶向疫苗一起施用可以介导大肿瘤的消退，这表明这些分子可能非常适合作为免疫佐剂。这项工作已提交出版。通过与病理学实验室Maria Tsokos博士的合作，我们观察到儿童肉瘤的肿瘤微环境中含有大量单核细胞（表达CD63和CD168）。在小鼠横纹肌肉瘤模型中，我们已经看到类似的骨髓细胞浸润，骨髓细胞具有免疫抑制表型，来自这些肿瘤的分选细胞可以抑制T细胞增殖。有趣的是，当给予DPP抑制剂时，这些细胞在表型和功能上被调节为较少的免疫抑制，这表明这种作用可能有助于这些分子的辅助特性。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。我们已经确定了第二代化合物，改善了小鼠的治疗窗口，增加了佐剂活性。我们已经开始与成人恶性肿瘤免疫学和生物学实验室的Jeff Schlom博士、James Gulley博士和Jim Hodge博士讨论这种药物的早期临床开发计划。霍奇医生的临床前研究还在进行吗？s实验室。此外，基于这些抑制剂在儿童肉瘤模型中的有效作用（如上所述），儿科肿瘤科正在考虑对儿童肉瘤进行单药研究。

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.