Transforming Human Pancreatic Cancer Into An Immunologic Disease

将人类胰腺癌转变为免疫疾病

• 批准号: 10661794
• 负责人: ELIZABETH M. JAFFEE
• 金额: $ 253.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661794
• 关键词: Acceleration; Achievement; Address; Animal Model; Animals; Antigens; Bioinformatics; Biological Assay; Biological Markers; Biometry; Bypass; Cell physiology; Cells; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Combined Modality Therapy; Complex; DNA analysis; Data; Databases; Dendritic Cells; Environment; Epigenetic Process; Exclusion; Feeds; Fibroblasts; Future; Generations; Genetic; Genomics; Granulocyte-Macrophage Colony-Stimulating Factor; Histone Deacetylase Inhibitor; Human; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immunotherapy; Incidence; Infiltration; Inflammation; Inflammatory; Interleukin-8; KRAS2 gene; Learning; Malignant Neoplasms; Malignant neoplasm of pancreas; Mus; Mutate; Mutation; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Oncogene Activation; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patients; Population; Procedures; Proteomics; RNA analysis; Reaction; Regulation; Regulatory T-Lymphocyte; Reporting; Research Design; Research Personnel; Resistance; Science; Signal Transduction; Source; Standardization; Stromal Cells; Survival Rate; T cell infiltration; T cell response; T cell therapy; T-Lymphocyte; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Tumor Immunity; Tumor-associated macrophages; Undifferentiated; Vaccines; angiogenesis; anti-CTLA4; anti-PD-1; arm; cell type; chemotherapy; combinatorial; data integration; design; digital pathology; effector T cell; genomic data; improved; innovation; monocyte; mouse model; multidisciplinary; neoantigen vaccine; neoantigens; novel; novel vaccines; pancreatic stellate cell; patient stratification; peripheral blood; pre-clinical; preclinical study; programs; recruit; standard of care; trafficking; translational clinical trial; treatment response; tumor; tumor microenvironment

Pancreatic ductal adenocarcinoma (PDA) is rising in incidence but remains deadly for most patients. Some progress has occurred in activating immune responses against PDA, however there are unanswered questions that need to be addressed for immunotherapy to have a significant impact on the lives of PDA patients. Our Team will address two critical problems: 1) inefficient generation of high quality T cells targeted against PDA antigens capable of tumor trafficking and killing; and 2) multiple cellular barriers that comprise stromal and myeloid cells that inhibit effector T cell trafficking and function in the PDA tumor microenvironment (TME). Both clinical studies (“science in patients”) and pre-clinical studies (mouse models) will be conducted to address these issues, and to evaluate novel combinatorial therapies that successfully modulate PDA stroma and chronic inflammation to facilitate improved tumor infiltration of high quality and durable cancer targeted T cells. This program is composed of 4 Projects and 4 Cores. The four projects will address the common overarching theme that PDA is composed of multiple cell types and signals that inhibit T cell induction, trafficking into, and function in tumors. Each project will address either the induction of quality T cells or the modulation of suppressive cell populations as major barriers to T cell infiltration and activation, and all will integrate agents that bypass these suppressive mechanisms with optimal T cell therapies. Projects 1, 2, and 4 will combine ongoing preclinical studies aimed at uncovering mechanisms of suppression of different barriers with translational clinical trials that study combination therapy to bypass these suppressive mechanisms. Project 3 will conduct a biomarker heavy clinical trial using a multi-arm Platform design that will add and delete immune modulatory arms based on data from biomarker analysis in this Project and from data that feeds into this Project from the other 3 Projects. Standard procedures will be used across Projects to collect and bank serial biospecimens obtained from patients treated on the clinical trials. The Cores will be critical for conducting the proposed assays and for analysis and integration of the data. A Program database will be developed to allow for integration of data generated from these assays across the entire Program. This will be a unique database that will also bring in data from other sources such as the TCGA database, and will provide the Program Team with the ability to compare results based on the genetics and inflammatory composition of each patient’s tumor and their response to the therapy they received. The final outcomes will include results from a number of therapeutic interventions, approaches to optimize each therapeutic, the potential to further integrate therapies that were tested in one or more projects in future trials, and the ability to develop TME signatures that may further stratify patients for therapeutic interventions. This program will substantially accelerate progress in PDA therapy, and allow otherwise nearly impossible achievements in defining predictors of successful immunological therapeutic intervention for PDAs.

胰腺导管腺癌（PDA）的发病率正在上升，但对大多数患者来说仍然是致命的。 在激活针对 PDA 的免疫反应方面已取得进展，但仍有一些问题尚未解答 免疫疗法需要解决这些问题才能对 PDA 患者的生活产生重大影响。 团队将解决两个关键问题：1）针对目标的高质量 T 细胞生成效率低下 能够运输和杀死肿瘤的 PDA 抗原；2) 包含基质的多重细胞屏障 以及抑制效应 T 细胞在 PDA 肿瘤微环境 (TME) 中运输和发挥作用的骨髓细胞。 将进行临床研究（“患者科学”）和临床前研究（小鼠模型）来解决 这些问题，并评估成功调节 PDA 基质和慢性病的新型组合疗法 炎症，以促进高质量和持久的癌症靶向 T 细胞改善肿瘤浸润。 该计划由 4 个项目和 4 个核心组成，这四个项目将解决共同的总体主题。 PDA 由多种细胞类型和抑制 T 细胞诱导、运输和功能的信号组成 每个项目都将解决优质 T 细胞的诱导或抑制性细胞的调节问题。 群体作为 T 细胞浸润和激活的主要障碍，所有这些都将整合绕过这些障碍的药物 项目 1、2 和 4 将结合正在进行的临床前研究，将抑制机制与最佳 T 细胞疗法结合起来。 旨在通过转化临床试验揭示抑制不同障碍的机制的研究 研究联合疗法绕过这些抑制机制 项目3将进行重生物标志物。 使用多臂平台设计的临床试验，将根据数据添加和删除免疫调节臂 来自该项目中的生物标志物分析以及其他 3 个项目输入该项目的数据。 整个项目将使用标准程序来收集和储存从患者获得的系列生物样本 临床试验中处理的核心对于进行拟议的分析和分析至关重要。 将开发一个程序数据库以允许集成从生成的数据。 这将是一个独特的数据库，也将引入来自其他项目的数据。 TCGA 数据库等来源，并将为项目团队提供比较结果的能力 基于每位患者肿瘤的遗传学和炎症成分以及他们对治疗的反应 他们收到的最终结果将包括许多治疗干预措施、方法的结果。 优化每种疗法，进一步整合在一个或多个项目中测试过的疗法的潜力 未来的试验，以及开发 TME 特征的能力，可以进一步对患者进行治疗分层 该计划将大大加速 PDA 治疗的进展，并允许几乎其他方面的治疗。 在定义 PDA 免疫治疗干预成功的预测因素方面取得了不可能的成就。

项目成果

A Random Forest Genomic Classifier for Tumor Agnostic Prediction of Response to Anti-PD1 Immunotherapy.

• DOI: 10.1177/11769351221136081
• 发表时间: 2022
• 期刊: CANCER INFORMATICS
• 影响因子: 2
• 作者: Bigelow, Emma;Saria, Suchi;Piening, Brian;Curti, Brendan;Dowdell, Alexa;Weerasinghe, Roshanthi;Bifulco, Carlo;Urba, Walter;Finkelstein, Noam;Fertig, Elana J.;Baras, Alex;Zaidi, Neeha;Jaffee, Elizabeth;Yarchoan, Mark
• 通讯作者: Yarchoan, Mark

High local failure rates despite high margin-negative resection rates in a cohort of borderline resectable and locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy following multi-agent chemotherapy.

• DOI: 10.1002/cam4.4527
• 发表时间: 2022-04
• 期刊: Cancer medicine
• 影响因子: 4
• 作者: Hill C;Sehgal S;Fu W;Hu C;Reddy A;Thompson E;Hacker-Prietz A;Le D;De Jesus-Acosta A;Lee V;Zheng L;Laheru DA;Burns W;Weiss M;Wolfgang C;He J;Herman JM;Meyer J;Narang A
• 通讯作者: Narang A

Refining the Molecular Framework for Pancreatic Cancer with Single-cell and Spatial Technologies.

• DOI: 10.1158/1078-0432.ccr-20-4712
• 发表时间: 2021-07-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Guo JA;Hoffman HI;Weekes CD;Zheng L;Ting DT;Hwang WL
• 通讯作者: Hwang WL

Post-radiation neutrophil-to-lymphocyte ratio is a prognostic marker in patients with localized pancreatic adenocarcinoma treated with anti-PD-1 antibody and stereotactic body radiation therapy.

• DOI: 10.3857/roj.2021.01060
• 发表时间: 2022-06
• 期刊: Radiation oncology journal
• 影响因子: 2.3

Tailoring Adjuvant Chemotherapy to Biologic Response Following Neoadjuvant Chemotherapy Impacts Overall Survival in Pancreatic Cancer.

• DOI: 10.1007/s11605-022-05476-w
• 发表时间: 2023-04
• 期刊: JOURNAL OF GASTROINTESTINAL SURGERY
• 影响因子: 3.2
• 作者: Ghabi, Elie M.;Shoucair, Sami;Ding, Ding;Javed, Ammar A.;Thompson, Elizabeth D.;Zheng, Lei;Cameron, John L.;Wolfgang, Christopher L.;Shubert, Christopher R.;Lafaro, Kelly J.;Burkhart, Richard A.;Burns, William R.;He, Jin
• 通讯作者: He, Jin