Transforming Human Pancreatic Cancer Into An Immunologic Disease

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。一些人 在激活针对PDA的免疫反应方面取得了进展，但仍有一些未回答的问题 免疫治疗需要解决这些问题，才能对PDA患者的生活产生重大影响。我们的 该团队将解决两个关键问题：1)针对以下目标的高质量T细胞的低效生成 能够转移和杀死肿瘤的PDA抗原；以及2)构成间质的多个细胞屏障 和髓系细胞，抑制效应T细胞在PDA肿瘤微环境(TME)中的运输和功能。 将进行临床研究(“患者中的科学”)和临床前研究(小鼠模型)，以解决 这些问题，并评估成功调节PDA间质和慢性 炎症有助于改善肿瘤的高质量和持久的抗癌靶向T细胞的渗透。这 该方案由4个项目和4个核心组成。这四个项目将涉及共同的总体主题 PDA由多种细胞类型和信号组成，它们抑制T细胞的诱导、运输和功能 在肿瘤中。每个项目都将涉及高质量T细胞的诱导或抑制细胞的调节 人群是T细胞渗透和激活的主要障碍，所有这些都将整合绕过这些障碍的药物 最佳T细胞疗法的抑制机制。项目1、2和4将结合正在进行的临床前工作 旨在通过转译临床试验揭示抑制不同屏障的机制的研究 研究联合疗法以绕过这些抑制机制。项目3将进行生物标记物重 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 从这个项目的生物标记物分析和从其他3个项目提供给这个项目的数据。 将在各个项目中使用标准程序来收集和存储从患者那里获得的连续生物检疫样本 在临床试验中接受治疗。岩心将对进行拟议的分析和分析至关重要 数据的集成。将开发一个方案数据库，以便整合从以下方面产生的数据 这些分析涵盖了整个项目。这将是一个唯一的数据库，它还将从其他数据库中引入数据 TCGA数据库等来源，并将为计划团队提供比较结果的能力 根据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，方法 优化每种疗法，进一步整合在一个或多个项目中测试的疗法的潜力 未来的试验，以及开发TME签名的能力，这可能会进一步对患者进行分层治疗 干预措施。这一计划将大大加快PDA治疗的进展，并允许在其他方面几乎 在定义成功的PDA免疫治疗干预的预测因素方面取得了不可能的成就。

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.