Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.

https://clincancerres.aacrjournals.org/content/clincanres/18/16/4266.full.pdf

The Pancreas Cancer Microenvironment

Only women with symptoms need to have their breast implants removed, says government

Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate immune suppression, but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T-cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics.

https://cancerres.aacrjournals.org/content/canres/74/18/5057.full.pdf

CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models

Cancer of the pancreas

Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21190

Recent Progress in Pancreatic Cancer

Pancreatic cancer remains the fourth leading cause of cancer related death in the United States.1 Surgical resection provides the only possibility of cure. However, the historical 5-year survival postresection remains approximately 15% to 20%, with 1 and 2-year survival of 63% and 42% respectively.2 A standard adjuvant treatment approach for patients with resected disease has not yet been determined.2–11

We developed irradiated GM-CSF transfected allogeneic whole cell tumor lines for pancreas ductal adenocarcinoma immunotherapy.12 We previously reported that this immunotherapy treatment administered intradermally in sequence with chemoradiotherapy to patients with resected pancreatic adenocarcinoma induced posttreatment delayed type hypersensitivity (DTH) responses to autologous tumor cells in 1 of 3 participants receiving 1 × 108 cells and in 2 of 5 participants receiving 5 × 108 vaccine cells. The 3 DTH responders are the only participants who remain disease-free at 10+ years. Importantly, immunized lymphocytes from the DTH-responders were used to screen a number of differentially expressed genes in pancreatic cancer. All 3 DTH responders demonstrated a postimmunotherapy T cell response to mesothelin, a glycosyl-phosphatidylinositol (GPI)-linked cell surface protein that likely serves as an adhesion molecule that promotes metastases.13–16

We now report the results of a single institution 60 patient phase II study testing the highest immunotherapy dose of GM-CSF secreting pancreatic tumor cells found to be safe and bioactive in phase I testing. This study was designed to estimate the disease-free and overall survival rates and the prevalence of mesothelin-specific T cell responses that are associated with immunotherapy treatment.

/pdf/a-lethally-irradiated-allogeneic-granulocyte-macrophage-1iita0oa13.pdf

A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma: A Phase II Trial of Safety, Efficacy, and Immune Activation

Miri Choi

Papers

A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma: A Phase II Trial of Safety, Efficacy, and Immune Activation