Re-wiring PDAC Tumor Immunity Through Dendritic Cells

项目总结 胰腺导管腺癌(PDAC)患者的预后很差。这很可能是由于 存在一种在大多数PDAC中占主导地位的独特的抑制性肿瘤微环境(TME)。我们的数据 提示常规树突状细胞(CDCs)的免疫启动可能是克服 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 回应。我们的新数据显示，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患者在 他们的骨髓，这导致循环前树突状细胞的功能衰竭，并对 检查点抑制药。2)我们最近发现，即使CDC发育没有完全受损，cDC1s 在物理/生物化学上被排除在PDAC TME之外。立体定向小体丢失的这些机制 放射治疗(SBRT)诱导的肿瘤抗原特异性T细胞反应的启动最终失败 动物模型中的肿瘤控制。我们克服了这两种功能障碍，通过使用一种 联合应用FMS样酪氨酸激酶3配体(Flt3L)和CD40激动剂进行全身治疗。我们的前- 临床数据异常强大，使我们处于独特的地位，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上对这一假设进行扩展检验。 目的1.确定CDX-301联合CDX-1140与SBRT联合应用的安全性和有效性。 局部晚期PDAC患者 目的2.确定Flt3L联合CD40激动剂诱导抗肿瘤免疫的机制。 目的3.确定Flt3L加CD40激动剂是否提高了对检查点的反应性 免疫疗法。 冲击力。PDAC患者对传统放射治疗的反应一直令人失望。我们的数据非常强大 支持使用Flt3L和CD40激动剂来增强患者对RT的反应性并产生长期的 抗肿瘤免疫。我们的团队处于有利地位，可以直接在临床和 实验研究。

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.