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）患者的预后很差。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 提示通过常规树突状细胞（cDC）免疫引发可能是克服 在PDAC患者中产生持久的免疫力。cDC是产生肿瘤抗原特异性T细胞的中心 应答我们的新数据表明，PDAC患者的cDC功能严重失调。这种功能障碍是 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，这导致循环前DC的功能耗尽，以及对 检查点抑制剂。2)我们最近发现，即使cDC发育没有完全受损，cDC 1 在物理/生物化学上被排除在PDAC TME之外。这些机制导致立体定向体的丢失 放射治疗（SBRT）诱导的肿瘤抗原特异性T细胞应答的启动，并最终失败 动物模型中的肿瘤控制。我们通过使用靶向cDC 1克服了这两个功能失调的障碍 与FMS样酪氨酸激酶3配体（FLT 3L）和CD 40激动剂的全身治疗组合。我们的预- 临床数据异常强大，使我们处于一个独特的位置，可以将这些发现转化为 PDAC患者我们的中心假设是，靶向cDC可以通过以下方式释放对RT的反应性： 产生持久的抗肿瘤免疫力。我们将在三个具体目标中扩展测试这一假设。 目标1。确定CDX-301加CDX-1140和SBRT联合治疗在 局部晚期PDAC患者 目标2.确定FLT 3L加CD 40激动剂诱导抗肿瘤免疫的机制。 目标3.确定FLT 3L加CD 40激动剂是否改善对检查点的反应性 免疫疗法 冲击PDAC患者对常规放射治疗的反应令人失望。我们的数据显示 支持使用FLT 3L和CD 40激动剂，以增强患者对RT的反应性，并产生长期 抗肿瘤免疫我们的团队处于有利地位，可以直接在临床和实验室中测试我们的中心假设。 实验研究