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。一些 在激活针对PDA的免疫反应方面已经取得了进展，但是仍有一些问题没有得到解答 免疫疗法需要解决的问题，对PDA患者的生活产生重大影响。我们 研究小组将解决两个关键问题：1）高质量T细胞的低效产生， 能够运输和杀伤肿瘤的PDA抗原;和2）包含基质的多个细胞屏障 以及抑制效应T细胞运输并在PDA肿瘤微环境（TME）中发挥功能的骨髓细胞。 将进行临床研究（“患者科学”）和临床前研究（小鼠模型）， 这些问题，并评估新的组合疗法，成功地调节PDA基质和慢性 炎症促进高质量和持久的癌症靶向T细胞的改善的肿瘤浸润。这 该计划由4个项目和4个核心组成。这四个项目将处理共同的首要主题 PDA由多种细胞类型和信号组成，这些细胞类型和信号抑制T细胞的诱导、运输和功能。 在肿瘤中。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， 作为T细胞浸润和活化的主要障碍，所有这些都将整合绕过这些障碍的药物。 抑制机制与最佳的T细胞疗法。项目1、2和4将结合联合收割机正在进行的临床前研究 旨在通过转化临床试验揭示不同屏障抑制机制的研究， 研究联合治疗以绕过这些抑制机制。项目3将进行生物标志物重 使用多组平台设计的临床试验，将根据数据添加和删除免疫调节组 来自本项目的生物标志物分析和来自其他3个项目的数据。 各项目将采用标准程序收集和储存从患者获得的系列生物标本 在临床试验中治疗。核心对于进行拟定的测定和分析至关重要， 数据的整合。将开发一个方案数据库，以便整合 在整个项目中进行这些检测这将是一个独特的数据库，也将带来来自其他数据库的数据。 来源，如TCGA数据库，并将为项目团队提供比较结果的能力 基于每个患者肿瘤的遗传学和炎症成分以及他们对治疗的反应， 他们收到了。最终结果将包括一些治疗干预的结果， 优化每种治疗方法，进一步整合在一个或多个项目中测试的治疗方法的潜力， 未来的试验，以及开发TME签名的能力，可以进一步对患者进行治疗分层 干预措施。这一计划将大大加快PDA治疗的进展，并允许其他近 在确定PDA成功免疫治疗干预的预测因子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