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: 8553086
• 负责人: Terry Fry
• 金额: $ 26.06万
• 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/8553086
• 关键词: Adjuvant; Adult; Amino Acids; CCL19 gene; CCL21 gene; Cancer Vaccines; Cell Separation; Cells; Childhood; Cleaved cell; Clinical; Clinical Trials; Collaborations; Data; Dendritic Cells; Development; Development Plans; Dipeptidyl Peptidases; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; FDA approved; Family; Generations; Goals; Immune; Immunologic Adjuvants; Immunologics; Immunosuppressive Agents; Infiltration; Injection of therapeutic agent; Laboratories; Malignant Neoplasms; Mediating; Modeling; Mus; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Pediatric Oncology; Peptides; Phase; Phenotype; Pre-Clinical Model; Property; Protease Inhibitor; Publications; Publishing; Rhabdomyosarcoma; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Tumor Biology; Vaccines; Work; base; cancer cell; cancer therapy; chemokine; glucagon-like peptide; improved; inhibitor/antagonist; lymph nodes; member; neoplastic cell; novel; preclinical study; prevent; prolyl oligopeptidase; receptor; sarcoma; selective expression; trafficking; tumor; tumor immunology

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.

我们已经确定，在包括儿科肉瘤模型在内的多种模型中，当在肿瘤注射后早期启动时，DPP的抑制可预防肿瘤发展。 这种效应是T细胞和树突状细胞（DC）依赖性的，并与加速肿瘤诱导的引发有关。 我们已经确定，DPP抑制可加速DC从肿瘤环境向引流淋巴结的运输，并且这种作用需要趋化因子CCL19和CCL21以及相关受体CCR7，这表明可能涉及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型肿瘤的消退，这表明这些分子可能非常适合作为免疫佐剂。我们与病理学实验室的Maria Tsokos博士合作，观察到小儿肉瘤的肿瘤微环境中含有大量的单核细胞（表达CD63和CD168）。 在横纹肌肉瘤的小鼠模型中，我们已经看到具有免疫抑制表型的髓样细胞的类似浸润，并且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低的免疫抑制性，这表明这种作用可能有助于这些分子的佐剂特性。 与Bill Bachovchin博士合作，我们现在正在我们的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，其在小鼠中具有改善的治疗窗口和增加的佐剂活性。 我们已经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。Hodge博士的临床前研究正在进行中？的实验室。 此外，基于这些抑制剂在儿科肉瘤模型中的强效作用（如上所述），儿科肿瘤分支正在考虑进行儿科肉瘤单药研究。