Re-wiring PDAC Tumor Immunity Through Dendritic Cells

通过树突状细胞重新连接 PDAC 肿瘤免疫

• 批准号: 10280010
• 负责人: David G DeNardo
• 金额: $ 55.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280010
• 关键词: Aftercare; Agonist; Animal Model; Animals; Antigens; Automobile Driving; Biochemical; Biological Assay; Biological Markers; Blood Circulation; Bone Marrow; Clinical; Clinical Data; Clinical Research; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Correlative Study; Cross Presentation; Cytometry; Cytotoxic agent; Data; Dendritic Cells; Development; Functional disorder; Future; Human; Image; Immune; Immune checkpoint inhibitor; Immunity; Immunologic Tests; Immunologics; Immunosuppression; Immunotherapy; Impairment; Infiltration; Ligands; Limes; Malignant Neoplasms; Malignant neoplasm of pancreas; Myelogenous; Nature; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Patients; Phase I/II Clinical Trial; Positioning Attribute; Prognosis; Radiation therapy; Reporting; Research; Research Personnel; Role; Safety; Signal Transduction; T cell response; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor-Derived; Tumor-infiltrating immune cells; Work; antigen-specific T cells; cancer cell; checkpoint therapy; chemotherapy; clinical translation; cohort; density; experimental study; fetal liver kinase-2; immune checkpoint blockade; immunosuppressive macrophages; improved; member; mouse model; pancreatic ductal adenocarcinoma model; patient response; pre-clinical; response; single cell analysis; treatment strategy; trial design; tumor; tumor microenvironment

PROJECT SUMMARY The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most PDAC. Our data suggest immune priming by conventional dendritic cells (cDCs) may be a necessary barrier to overcome to generate lasting immunity in PDAC patients. cDCs are central for generating tumor antigen–specific T cell responses. Our new data show that cDCs are severely dysfunctional in patients with PDAC. This dysfunction is driven by two mechanisms: 1) We recently reported that PDAC patients have impaired cDC development in their bone marrow, and this leads to functional depletion of circulation pre-DCs, and poor response to checkpoint inhibitors. 2) We recently showed that even when cDC development is not fully impaired, cDC1s are physically/biochemically excluded from the PDAC TME. These mechanisms to the loss of stereotactic body radiation therapy (SBRT)-induced priming of tumor antigen-specific T cell responses and ultimately failed tumor control in animal models. We overcame both of these dysfunctional barriers by targeting cDC1s using a combination of systemic treatment with FMS-like tyrosine kinase 3 ligand (FLT3L) and CD40 agonists. Our pre- clinical data are exceptionally strong and have placed us in a unique position to translate these findings into PDAC patients. Our central hypothesis is that targeting cDC can unlock responsiveness to RT by generating lasting anti-tumor immunity. We will expand test this hypothesis in three specific aims. Aim 1. Determine the safety and efficacy of the combination of CDX-301 plus CDX-1140 and SBRT in locally advanced PDAC patients Aim 2. Determine the mechanisms by which FLT3L plus a CD40 agonist induce anti-tumor immunity. Aim 3. Determine if FLT3L plus CD40 agonists improves responsiveness to checkpoint immunotherapy. Impact. PDAC patient responses to conventional radiation therapy have been disappointing. Our data strongly support the use of FLT3L and CD40 agonist to enhance patient responsiveness to RT and generate long-term anti-tumor immunity. Our team is well-positioned to test our central hypothesis directly in clinical and experimental studies.

项目摘要 胰腺导管腺癌（PDAC）患者的预后很沮丧。这可能是由于 在大多数PDAC中占主导地位的独特抑制性肿瘤微环境（TME）的存在。我们的数据 建议通过常规树突状细胞（CDC）免疫启动可能是克服的必要障碍 PDAC患者产生持久的免疫力。 CDC是生成肿瘤抗原特异性T细胞的中心 回答。我们的新数据表明，PDAC患者的CDC严重功能失调。这种功能障碍是 在两种机制的驱动下：1）我们最近报告说，PDAC患者在CDC的发展受损 它们的骨髓，这导致循环前-DC的功能耗竭，对 检查点抑制剂。 2）我们最近表明，即使CDC开发没有完全损害，CDC1也 在物理/生化上排除在PDAC TME中。这些机制损失了立体定向的身体 放射疗法（SBRT）诱导的肿瘤抗原特异性T细胞反应的启动，并最终失败 动物模型中的肿瘤控制。我们通过使用A靶向CDC1来克服这两个功能失调的障碍 全身处理与FMS样酪氨酸激酶3配体（FLT3L）和CD40激动剂的组合。我们的前 临床数据异常强大，并使我们处于将这些发现转化为独特的位置 PDAC患者。我们的核心假设是，靶向CDC可以通过 产生持久的抗肿瘤免疫力。我们将在三个特定目标中扩展这一假设。 目标1。确定CDX-301加CDX-1140和SBRT组合的安全性和效率 本地高级PDAC患者 AIM 2。确定FLT3L加上CD40激动剂诱导抗肿瘤免疫组分的机制。 目标3。确定FLT3L加CD40激动剂是否提高了对检查点的响应能力 免疫疗法。 影响。 PDAC患者对常规放射疗法的反应令人失望。我们的数据强烈 支持使用FLT3L和CD40激动剂来增强患者对RT的反应并产生长期 抗肿瘤免疫。我们的团队有很好的位置，可以直接在临床和 实验研究。