Re-wiring PDAC Tumor Immunity Through Dendritic Cells

通过树突状细胞重新连接 PDAC 肿瘤免疫

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胰腺导管腺癌（PDAC）患者的预后很差，这可能是由于以下原因。存在独特的抑制性肿瘤微环境 (TME)，该微环境在我们的大多数 PDAC 数据中占主导地位。表明传统树突状细胞（cDC）的免疫启动可能是克服的必要障碍在 PDAC 患者中产生持久的免疫力对于产生肿瘤抗原特异性 T 细胞至关重要。我们的新数据表明，PDAC 患者的 cDC 功能严重失调。由两种机制驱动：1）我们最近报道 PDAC 患者的 cDC 发育受损他们的骨髓，这会导致循环前 DC 的功能衰竭，并且对 2) 我们最近表明，即使 cDC 发育没有完全受损，cDC1 也会发生变化。这些机制在物理/生物化学上被排除在 PDAC TME 之外。放射治疗 (SBRT) 诱导启动肿瘤抗原特异性 T 细胞反应并最终失败我们通过使用靶向cDC1克服了动物模型中的肿瘤控制。 FMS 样酪氨酸激酶 3 配体 (FLT3L) 和 CD40 激动剂的全身治疗相结合。临床数据非常有力，使我们处于独特的地位，可以将这些发现转化为我们的中心假设是，靶向 cDC 可以通过以下方式释放对 RT 的反应：我们将在三个特定目标上扩展测试这一假设。目标 1. 确定 CDX-301 加 CDX-1140 和 SBRT 联合治疗的安全性和有效性局部晚期 PDAC 患者目标 2. 确定 FLT3L 联合 CD40 激动剂诱导抗肿瘤免疫的机制。目标 3. 确定 FLT3L 加 CD40 激动剂是否可以改善对检查点的反应免疫疗法。影响 PDAC 患者对传统放射治疗的反应非常令人失望。支持使用 FLT3L 和 CD40 激动剂来增强患者对 RT 的反应并产生长期我们的团队有能力在临床和临床中直接检验我们的中心假设。实验研究。