Rapid evaluation of immunotherapy regimens in ex vivo human pancreatic tumor slice cultures.

快速评估离体人胰腺肿瘤切片培养物中的免疫治疗方案。

基本信息

批准号：
10312775
负责人：
Hidayatullah G. Munshi
金额：
$ 18.33万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312775
关键词：
Antibodies Architecture Biochemical CD8-Positive T-Lymphocytes CTLA4 gene Cells Cellular immunotherapy Clinical Clinical Research Clinical Trials Combination immunotherapy Combined Modality Therapy Complex Development Elements Epigenetic Process Evaluation Future Goals Human Human Biology Immune Immune checkpoint inhibitor Immune response Immunotherapy Lead Mission Modeling Morphology Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Phase Pre-Clinical Model Proteins Public Health Rapid screening Regimen Reporting Research Slice Solid Neoplasm T-Lymphocyte Testing Transgenic Mice Treatment Protocols Tumor-infiltrating immune cells United States National Institutes of Health base cancer cell cell killing chemokine cytokine efficacy evaluation expectation improved improved outcome in vivo innovation interest mouse model novel pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic neoplasm preservation programmed cell death ligand 1 programmed cell death protein 1 response small molecule inhibitor targeted treatment tumor tumor microenvironment tumor-immune system interactions

项目摘要

There is an urgent need to evaluate immunotherapy combination regimens in pre-clinical models that faithfully represent the complex biology of human pancreatic ductal adenocarcinoma (PDAC) tumors. Since ex vivo human PDAC tumor slice cultures maintain the tumor morphology, stromal architecture, and immune cell composition of in vivo PDAC tumors, slice cultures have potential utility in the rapid screening of immunotherapy combination regimens for PDAC. The main objective in this application is to use human PDAC tumor slice cultures to identify combination regimens that enhance the response to immune checkpoint inhibitors in PDAC. The central hypothesis is that human PDAC tumor slice cultures will allow for rapid evaluation and mechanistic characterization of novel immunotherapy combination regimens against PDAC. Two specific aims are proposed: 1) Screen combination regimens in human pancreatic tumor slice cultures; and 2) Characterize the mechanisms by which the effective combination therapies promote immune responses in pancreatic tumors. Under the first aim, novel combination regimens with epigenetic and immune checkpoint inhibitors will be tested in human PDAC tumor slice cultures using small molecule inhibitors and antibodies that are currently in early phase human studies. The ability of these regimens to enhance cytolytic CD8+ T cell infiltration and function will be evaluated to identify the regimens most effective at cancer cell killing. In the second aim, the mechanisms by which the effective combination regimens successfully overcome immune, biochemical, and physical barriers to CD8+ T cell infiltration and function will be characterized. The extent to which the effective combination regimens decrease immunosuppressive cells, cytokines, and chemokines will be evaluated. The extent to which the effective combination regimens enhance the spatial interaction between CD8+ T cells and cancer cells to promote successful cancer cell killing will also be evaluated. There are several innovative elements in this proposal, including the combination of checkpoint inhibitors with small molecule inhibitors that have not been previously evaluated together, and the use of ex vivo slice cultures of human PDAC tumors to rapidly evaluate efficacy of immunotherapy regimens. This proposed research is significant because it will have important clinical- translational implications and should result in the development of mechanism-based novel combination therapies for PDAC.

迫切需要在临床前模型中评估免疫治疗联合方案，以忠实地代表了人类胰腺导管腺癌（PDAC）肿瘤的复杂生物学。由于离体人 PDAC 肿瘤切片培养物维持肿瘤形态、基质结构和免疫细胞体内 PDAC 肿瘤的组成，切片培养在免疫治疗的快速筛选中具有潜在用途 PDAC 的联合治疗方案。本应用的主要目标是使用人类 PDAC 肿瘤切片培养物以确定增强 PDAC 对免疫检查点抑制剂反应的联合方案。中心假设是人类 PDAC 肿瘤切片培养物将允许快速评估和机制针对 PDAC 的新型免疫治疗组合方案的表征。提出了两个具体目标： 1) 在人胰腺肿瘤切片培养中筛选联合方案； 2) 表征机制有效的联合疗法可促进胰腺肿瘤的免疫反应。在第一个下目标是，表观遗传和免疫检查点抑制剂的新型组合方案将在人体中进行测试使用目前处于早期人类阶段的小分子抑制剂和抗体进行 PDAC 肿瘤切片培养研究。将评估这些方案增强溶细胞性 CD8+ T 细胞浸润和功能的能力以确定最有效杀死癌细胞的方案。在第二个目标中，有效的联合方案成功克服了 CD8+ T 的免疫、生化和物理障碍将表征细胞浸润和功能。联合治疗方案的有效程度将评估免疫抑制细胞、细胞因子和趋化因子的减少。的程度有效的联合方案增强 CD8+ T 细胞和癌细胞之间的空间相互作用促进成功杀死癌细胞的作用也将得到评估。这其中有很多创新元素提案，包括检查点抑制剂与尚未被批准的小分子抑制剂的组合先前一起评估，并使用人类 PDAC 肿瘤的离体切片培养物来快速评估免疫治疗方案的疗效。这项拟议的研究意义重大，因为它将具有重要的临床意义转化意义并应导致基于机制的新型联合疗法的开发对于 PDAC。