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

项目摘要-项目3 摘要胰腺导管腺癌(Pda)以密集的促结缔组织增生和免疫抑制为特征。 间质仍然是联合免疫治疗方法的障碍。我们的团队已经开发出了 测试一种分泌GM-CSF的同种异体全细胞疫苗(GVAX)与一种分泌间硫蛋白的李斯特菌相结合 以单核细胞增多为基础的疫苗(CRS-207)在Prime-Boost策略中可以诱导高质量的T细胞， 渗透进掌上电脑。在早期的临床研究中观察到了有希望的活性；然而，一项随机的2b期研究 对严重预治疗的转移性PDA患者进行此策略与化疗的比较 终结点。有趣的是，这项研究的生物标记物分析和GVAX的新佐剂测试单独证明了 T细胞渗入PDA，随后免疫检查点上调，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) 正在渗入的髓样细胞。我们还观察到免疫抑制髓系细胞和基质细胞之间的相关性。 髓系趋化因子，如CXCR4、CXCR2、CCR2与预后。一项正在进行的临床试验，其中包括抗- PD-1和抗CTLA-4在既往治疗的转移性PDA患者中应用PRIME/BOOST疫苗的结果 一些持久的回应。因此，这个项目将检验中心假说，即基质-髓系 隔室仍然是有效的抗肿瘤反应和联合免疫治疗方法的障碍 将需要一种T细胞诱导疫苗CTLA-4和PD-1途径的抑制剂以及 目标是髓系间质间的串扰。确定髓系-基质信号轴及其与T细胞的关系 细胞反应，我们将首先对患者肿瘤和周围的髓系细胞和T细胞进行深度剖析 参与使用GVAX/CRS-207和免疫检查点抑制剂的三项互补临床试验 (ICI)治疗。此外，我们将采用一种新的平台试验设计来快速测试不同的骨髓基质 以ICI/-疫苗为靶标的疫苗平行或顺序进行。第一个子协议已准备就绪，并且 将在先前数据的基础上测试抗PD-1和抗CXCR4通路。我们将在基线和以后收集活组织检查 治疗并确定这些药物对髓系和间质细胞以及T细胞的确切影响 在肿瘤和外周的激活。生成的数据将被共享，以通知其他3个项目。此外, 每个项目的优化代理将被合并到新的子协议中，以便在我们的平台试验中进行测试。 最终交付的是与ICIS和基质-髓样细胞一起给予的T细胞诱导剂的优化组合 显示临床反应并可在多中心临床试验中验证的重新编程药物。

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.