Development of dipeptidyl peptidase inhibitors as novel immune adjuvants

二肽基肽酶抑制剂作为新型免疫佐剂的开发

• 批准号: 8349450
• 负责人: Terry Fry
• 金额: $ 16.59万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349450
• 关键词: Adjuvant; Adoptive Transfer; Adult; Amino Acids; Antigen-Presenting Cells; Blood; CCL19 gene; CCL21 gene; Cancer Vaccines; Cell physiology; Childhood; Cleaved cell; Clinical; Clinical Trials; Collaborations; Data; Dendritic Cells; Development; Development Plans; Dipeptidyl Peptidases; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; FDA approved; Family; Generations; Goals; Hematologic Neoplasms; Human; Immune; Immunologic Adjuvants; Immunologics; Injection of therapeutic agent; Interleukin-17; Laboratories; Malignant Neoplasms; Marrow; Mediating; Memory; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome Study; Pediatric Oncology; Peptides; Phase; Population; Pre-Clinical Model; Protease Inhibitor; Publishing; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Transplantation; Tumor Biology; Tumor-Associated Process; Vaccination; Vaccine Adjuvant; Vaccines; base; cancer cell; cancer therapy; chemokine; cytokine; glucagon-like peptide; improved; lymph nodes; member; novel; prevent; prolyl oligopeptidase; receptor; research study; sarcoma; selective expression; trafficking; tumor; tumor growth; tumor immunology

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).

我们已经确定，在多个模型中，在肿瘤注射后早期开始抑制 DPP 可以预防肿瘤的发展。有趣的是，这种消退发生在肿瘤生长的初始阶段之后，即使在肿瘤大小达到峰值时停止 DPP 抑制也能观察到这种消退。通过耗竭实验和肿瘤再攻击已经确定了对 T 细胞的需求和选择性记忆的诱导。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 细胞的数量，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，经 DPP 抑制剂治疗的荷瘤小鼠的 T 细胞在过继转移至淋巴细胞减少的小鼠中后介导了更好的抗肿瘤作用。值得注意的是，即使在过继转移后没有施用额外的 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。尽管 DPP 抑制剂治疗增加了产生 IL-17 的 T 细胞（已知具有有效抗肿瘤活性的群体）的数量，但在缺乏 IL-17 或 IL-23p19（从 Giorgio Trinchieri 博士获得）的小鼠中，肿瘤消退保持完整，IL-23p19 是一种细胞因子，对产生 IL-17 的 TC 细胞功能也很重要。通过选择性清除抗原呈递细胞，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，还需要树突状细胞。与肿瘤加速 T 细胞启动一致，DPP 抑制剂治疗导致 DC 加速运输至肿瘤引流淋巴结。在缺乏负责 DC 运输至肿瘤引流淋巴结的趋化因子 CCL19 和 CCL21 的 plt/plt 小鼠中，抗肿瘤活性丧失。此外，初步数据表明暴露于 DPP 抑制剂的淋巴结 CCL19 的分泌增加。正在进行的研究正在使用 DC 上缺乏 CCL19/21 受体 CCR7 的小鼠来证实这些结果。最后，尽管肿瘤攻击后稍后开始 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 疫苗接种的组合可导致多种肿瘤模型（包括儿童肉瘤模型）中已建立的大型肿瘤消退。因此，我们的研究表明，DPP 抑制剂代表了有效的疫苗佐剂，具有针对 DC 的新颖作用机制，并且预计会与直接针对肿瘤特异性 T 细胞（如细胞因子）的药物产生协同作用。我们现在与 Bill Bachovchin 博士合作，在肿瘤疫苗模型中测试多种 DPP 抑制剂，选择性靶向不同的 DPP 酶。我们已经鉴定出一种第二代化合物，可以改善小鼠的治疗窗并增加佐剂活性。我们已开始与成人恶性肿瘤肿瘤免疫学和生物学实验室的 Jeff Schlom 博士、James Gulley 博士和 Jim Hodge 博士讨论该药物的早期临床开发计划。根据这些研究的结果，儿科肿瘤科将考虑使用已经在人体中测试的疫苗平台进行后续试验（实体瘤疫苗与 Crystal Mackall 博士合作，血液恶性肿瘤疫苗通过血液和骨髓移植科（参见 ZIA BC 011295 项目）与 Alan Wayne 博士合作）。