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

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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.