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: 9780735
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9780735
• 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 (PDAC) 的风险增加到更高的水平 与普通民众相比，退伍军人迫切需要提高有效性 最近，癌症免疫疗法为退伍军人管理局的退伍军人提供了治疗 PDAC 的方法。 在多种癌症中显示出巨大的前景，但在 PDAC 中却没有。 PDAC 的异质性以及缺乏针对个体肿瘤亚型的免疫治疗。 PDAC 患者治疗分层仍处于起步阶段，是一种可靠的方法 对复杂肿瘤成分进行解卷积以对 PDAC 亚型进行分层的方法尚未得到认可。 最近，我们参与了PDAC标本的全基因组测序，提供了 根据基因组结构模式将 PDAC 分为四种亚型的基础 其中，免疫原性亚型占 178 个变异的 30%（Nature，2016）。 PDAC样本在TCGA数据库中，其特点是免疫细胞上调 网络，这可能表明对免疫疗法的不同反应。 表观基因组解卷积 (EDec) 方法，首先由我们的合作研究员 Dr. Milosavljevic 的小组提供了有关肿瘤细胞类型组成的宝贵信息， 细胞类型特异性基因表达（Cell Rep. 2016）当应用于免疫原性亚型时。 PDAC 肿瘤，EDec 揭示了一个免疫抑制微环境，其特征是 属于免疫原性的所有四种亚型癌细胞中 Foxp3 表达最高。 亚型也表现出最高的间皮素 (MSLN) 表达，因此，我们捕获了这一点。 具有免疫原性的 PDAC 可能是响应的目标亚群 通过 MSLN 病毒样颗粒 (VLP) 疫苗接种或联合治疗进行免疫治疗 VLP 和免疫检查点抑制剂我们将在临床前动物中检验我们的假设。 最能概括人类 PDAC 患者对免疫治疗反应的模型，包括 我们的初步数据是患者来源的肿瘤异种移植物（PDX）和人源化小鼠模型。 已表明我们的抗 MSLN VLP 疫苗可有效对抗 MSLN 高表达的 PDX 基于我们强有力的初步结果，我们建立了人源化 NSG 小鼠模型（PDX-hu-NSG）。 提出通过结合三种高度结合来开发有效的癌症免疫治疗方法 协同创新：（1）一种新颖的表观遗传反卷积方法来分层PDAC肿瘤； （2）PDX-hu-NSG模型；（3）MSLN-VLP疫苗与抗PD-1的联合治疗 我们提出了两个具体目标，在目标1中，我们将确定是否具有免疫原性。 PDAC 亚型对 PDX-hu-NSG 模型中的 MSLN-VLP 疫苗有反应。 使用 EDec 方法按亚型对 VA PDAC 进行分层，然后确定 MSLN-VLP 疫苗 在目标 2 中，我们将研究人源化 PDX 小鼠模型中特定 PDAC 亚组的功效。 确定抗 PD-1 Ab 联合治疗是否可以增强 MSLN VLP 疫苗的效果 我们还将确定特定的肿瘤浸润。 负责有效联合治疗的细胞子集。 联合治疗的副作用也将得到评估，我们的研究结果将提供临床前信息。 创新精准免疫疗法治疗 PDAC 的疗效评估 该项目将提供对小鼠的人性化而不会将患者置于危险之中的理解。 分子、细胞和组织水平对治疗的反应，这是改善治疗的关键一步 通过患者分层治疗来评估 PDAC 的结果。