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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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. 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，在多种模型中，肿瘤注射后早期启动时，对DPP的抑制会阻止肿瘤发育。有趣的是，这种回归发生在最初的肿瘤生长期之后，即使在峰值肿瘤大小下停止DPP抑制作用，也会观察到。使用耗竭实验和肿瘤补偿确定了T细胞的需求和选择性记忆的诱导。此外，我们已经证明了DPP抑制剂治疗不会增加肿瘤自然诱导的T细胞的大小，而是会加速肿瘤启动过程，从而导致肿瘤早期肿瘤反应性T细胞的增加。有趣的是，与未接受DPP抑制剂的肿瘤小鼠的T细胞相比，来自含有肿瘤的DPP抑制剂治疗的小鼠的T细胞会介导超肿瘤的上等抗肿瘤作用。值得注意的是，即使在收养转移后未施用其他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IL-17产生的T细胞的数量，但已知具有有效抗肿瘤活性的人群，但在小鼠中肿瘤的消退仍然完好无损，缺乏IL-17或IL-23P19（从Giorgio Trinchieri博士获得），这是一种在IL-17的细胞因子，在IL-17中也很重要。使用抗原呈递细胞的选择性耗竭，我们已经证明，除了对DPP抑制剂介导的肿瘤消退的T细胞需求外，还需要树突状细胞。与通过肿瘤加速的T细胞启动一致，DPP抑制剂治疗导致DC加速对肿瘤排出淋巴结的运输。抗肿瘤活性在PLT/PLT小鼠中丧失，缺乏导致肿瘤排出淋巴结CCL19和CCL21的DC运输的趋化因子。此外，初步数据表明，暴露于DPP抑制剂的淋巴结对CCL19的分泌增加。正在进行的研究正在使用DCS上CCL19/21的受体中缺乏受体CCR7的受体的小鼠证实了这些结果。最后，尽管肿瘤挑战后后来对DPP抑制剂治疗的启动并不能阻止肿瘤的生长，但DPP抑制剂与靶向肿瘤的DC疫苗接种的组合导致多种肿瘤模型中大型已建立的肿瘤的消退，包括小儿肉瘤模型。因此，我们的研究表明，DPP抑制剂具有具有新型作用机理的有效疫苗佐剂，该辅助机理靶向DC，并将与直接靶向肿瘤特异性T细胞（如细胞因子）的剂协同作用。与Bill Bachovchin博士合作，我们现在正在测试在肿瘤疫苗模型中选择性靶向不同DPP酶的多个DPP抑制剂。我们已经确定了一种第二代化合物，具有改善的小鼠治疗窗口并增加了辅助活性。我们已经开始与Jeff Schlom博士，James Gulley博士和Jim Hodge博士在成人恶性肿瘤的肿瘤免疫学和生物学实验室中讨论该代理的早期临床发展计划。根据这些研究的结果，将在小儿肿瘤学分支中使用已经在人类中进行了测试的疫苗平台（实体肿瘤疫苗与Crystal Mackall博士合作，并通过血液和割草机与骨髓移植部门合作（请参阅ZIA BC 011295 Projection bc 011295）和Alan Wayne）。