A precision oncology approach to integrating of tumor microenvironment suppressive cell modulators to enhance antitumor immunity

项目摘要-项目3 胰腺导管腺癌（PDA）的特征是致密促纤维增生和免疫抑制。 间质仍然是甚至联合免疫治疗方法的障碍。我们的团队已经发展， 测试了分泌GM-CSF的同种异体全细胞疫苗（GVAX）与分泌间皮素的巨噬细胞疫苗的组合， 单核细胞生成素疫苗（CRS-207）在初免-加强免疫策略中，可以诱导高质量的T细胞， 潜入PDA在早期临床研究中观察到有希望的活性;然而，一项随机2b期研究 将该策略与化疗在重度预治疗的转移性PDA患者中进行比较， 终点。有趣的是，这项研究的生物标志物分析和单独的GVAX新辅助试验表明， T细胞浸润PDA，随后上调免疫检查点，如程序性细胞死亡 蛋白1（PD-1）及其配体（PD-L1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）， 骨髓细胞浸润我们还观察到免疫抑制性骨髓细胞和间质细胞之间的相关性。 骨髓趋化因子，例如CXCR 4、CXCR 2、CCR 2和结果。一项正在进行的临床试验， PD-1和抗CTLA-4联合初免/加强疫苗治疗既往接受过治疗的转移性PDA患者， 一些持久的反应。因此，该项目将测试中心假设，即基质-髓系 隔室仍然是有效抗肿瘤反应和联合免疫治疗方法的障碍 将需要T细胞诱导疫苗+CTLA-4和PD-1途径的抑制剂以及 靶向骨髓基质串扰。为了确定骨髓基质细胞信号轴及其与T细胞的关系， 细胞反应，我们将首先对患者肿瘤和外周中的骨髓和T细胞进行深度分析 参与三项使用GVAX/CRS-207和免疫检查点抑制剂的互补临床试验 (ICI)治疗此外，我们将采用一种新的平台试验设计来快速检测不同的骨髓基质细胞， 靶向剂与ICI +/-疫苗平行或顺序施用。第一子协议准备好累积， 将在先前数据的基础上检测抗PD-1和抗CXCR 4通路。我们将在基线和基线时收集活检样本， 治疗，并确定这些药物对骨髓和基质细胞群，以及对T细胞 在肿瘤和周围激活。生成的数据将被共享，以通知其他3个项目。此外，本发明还提供了一种方法， 来自每个项目的优化代理将被纳入新的子协议中，用于我们的平台试验。 最终可交付的是T细胞诱导剂与ICI和基质-髓样细胞的优化组合。 重编程剂显示出临床反应并且可以在多中心临床试验中验证。

Project Abstract – Project 3 Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense desmoplastic and immunosuppressive stroma which remains a barrier to even combination immunotherapy approaches. Our group has developed and tested a GM-CSF secreting allogeneic whole cell vaccine (GVAX) combined with a mesothelin-secreting listeria monocytogenes-based vaccine (CRS-207) in a prime-boost strategy that can induce high quality T cells that infiltrate PDAs. Promising activity was observed in early clinical studies; however, a randomized phase 2b study comparing this strategy to chemotherapy in heavily pretreated patients with metastatic PDA failed to meet its endpoint. Interestingly, biomarker analyses from this study and neoadjuvant testing of GVAX alone demonstrated T cell infiltration into PDAs with subsequent upregulation of immune checkpoints such as programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) on PDA and infiltrating myeloid cells. We also observed a correlation between immunosuppressive myeloid cells and stromal- myeloid chemokines, e.g. CXCR4, CXCR2, CCR2, and outcomes. An ongoing clinical trial incorporating anti- PD-1 and anti-CTLA-4 with prime/boost vaccines in patients with previously treated metastatic PDA has yielded a few durable responses. Thus, this project will test the central hypothesis that the stromal-myeloid compartment remains a barrier to effective anti-tumor response and combination immunotherapy approaches will require a T cell inducing vaccine + inhibitors of the CTLA-4 and PD-1 pathway together with agents that target myeloid-stromal cross-talk. To determine the myeloid-stromal signaling axes and their relationship to T cell responses, we will first perform deep profiling of myeloid and T cells in the tumors and periphery of patients participating in three complementary clinical trials employing GVAX/CRS-207 and immune checkpoint inhibitor (ICI) therapies. Additionally, we will employ a novel platform trial design to rapidly test different myeloid-stromal targeting agents with ICI +/- vaccines in parallel or sequentially. The first sub-protocol is ready to accrue and will test anti-PD-1 and anti-CXCR4 pathways building on prior data. We will collect biopsies at baseline and on treatment and determine the precise effects of these agents on myeloid and stromal populations, and on T cell activation in tumor and in the periphery. Data generated will be shared to inform the other 3 Projects. In addition, optimized agents from each project will be incorporated into new sub-protocols for testing in our Platform trial. The final deliverable is an optimized combination of T cell inducing agents given with ICIs and stromal-myeloid reprogramming agents that show clinical responses and can be validated in a multicenter clinical trial.