Stratification of Pancreatic Cancer Subpopulations for Effective Immunotherapy

胰腺癌亚群分层以实现有效的免疫治疗

• 批准号: 10041691
• 负责人: Qizhi C. Yao
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10041691
• 关键词: Animal Model; Biological Markers; Cells; Combined Modality Therapy; Complex; Data; Databases; Epigenetic Process; FOXP3 gene; Gene Expression; General Population; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immunotherapy; Individual; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Modeling; Molecular; Nature; Pancreatic Ductal Adenocarcinoma; Patients; Pattern; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Specimen; Stratification; Subgroup; System; Testing; The Cancer Genome Atlas; Tissues; Treatment Efficacy; Tumor Subtype; Tumor-Derived; Vaccination; Vaccines; Variant; Veterans; Virus-like particle; anti-PD1 antibodies; base; cancer cell; cancer immunotherapeutics; cancer immunotherapy; cell type; cohort; effective therapy; efficacy evaluation; epigenomics; falls; genome sequencing; humanized mouse; immunogenic; improved outcome; infancy; innovation; mesothelin; mouse model; nano-string; neoplastic cell; novel; patient response; patient stratification; personalized immunotherapy; pre-clinical; preclinical evaluation; response; side effect; specific biomarkers; structural genomics; tumor; tumor xenograft; tumor-immune system interactions; vaccine efficacy; vaccine response; whole genome

As the risk for pancreatic ductal adenocarcinoma (PDAC) has increased to a higher rate in veterans relative to that in the general population, there is an urgent need to develop effective therapies to treat PDAC for veterans in the VA system. Recently, cancer immunotherapy has shown great promise in several cancers, but not in PDAC. Part of the reason for this is the heterogeneity of PDAC and lack of tailoring of immunotherapy to individual tumor subtypes. PDAC patient stratification for therapy remains in its infancy, and a reliable method to deconvolute complex tumor composition to stratify PDAC subtypes has not been recognized. Recently, we participated in whole genome sequencing of PDAC specimens, which provides the basis for classifying PDAC into four subtypes based upon patterns of genomic structural variation (Nature, 2016). Among these, the immunogenic subtype accounts for 30% of 178 PDAC samples in the TCGA database and is characterized by upregulated immune cell networks, which could indicate differential responses to immunotherapy. In addition, the Epigenomic Deconvolution (EDec) method, first developed by our co-investigator Dr. Milosavljevic’s group, provides valuable information about cell type composition of tumors and cell-type specific gene expression (Cell Rep. 2016). When applied to immunogenic subtype PDAC tumors, EDec reveals an immunosuppressive microenvironment characterized by the highest Foxp3 expression among all four subtypes. Cancer cells falling into the immunogenic subtype also show the highest mesothelin (MSLN) expression. Therefore, we hypothesize that PDACs with an immunogenic profile could be a target subgroup that is responsive to immunotherapy either by MSLN virus-like particle (VLP) vaccination or combination therapy of VLPs and an immune checkpoint inhibitor. We will test our hypothesis in pre-clinical animal models that best recapitulate human PDAC patient’s response to immunotherapy, including patient-derived tumor xenografts (PDX) and humanized mouse models. Our preliminary data have shown that our anti-MSLN VLP vaccine is effective against MSLN-high expressing PDX in a humanized NSG mouse model (PDX-hu-NSG). Based on our strong preliminary results, we propose to develop an effective cancer immunotherapeutic approach by combining three highly synergistic innovations: (1) A novel epigenetic deconvolution method to stratify PDAC tumors; (2) PDX-hu-NSG models; and (3) Combination therapy of MSLN-VLP vaccine plus anti-PD-1 antibody. We propose two specific aims. In Aim 1, we will determine whether the immunogenic subtype of PDAC is responsive to MSLN-VLP vaccine in PDX-hu-NSG model. Here, we will use EDec method to stratify VA PDACs by subtype and then determine MSLN-VLP vaccine efficacy in specific PDAC subgroups in humanized PDX mouse model. In Aim 2, we will determine whether combination therapy with anti-PD-1 Ab enhances MSLN VLP vaccine responses and efficacy in onco-humice model. We will also determine specific tumor infiltrating subset of cells that are responsible for the effective combination therapy. Furthermore, potential side-effect of the combination therapy will also be evaluated. Our findings will provide preclinical evaluation of the therapeutic efficacy of an innovative precision immunotherapy for PDAC in humanized mice without putting patients at risk. The project will provide understanding of molecular, cellular, and tissue-level responses to therapy, a key step towards improved outcomes in PDAC through patient stratification for therapy.

随着胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）的发病率增高