Abstract PR9: Granulocyte macrophage colony stimulating factor (GM-CSF) pancreas tumor vaccine in combination with blockade of PD-1 in a preclinical model of pancreatic cancer.
Authors: Soares Kevin C. , Olino Kelly , Edil Barish , Zhou Donger , Wamwea Anthony , Leubner Ashley , Schulick Richard , Pardoll Drew , Jaffee Elizabeth , Zheng Lei 
Published: August 2014

Introduction: Our phase I/II human clinical trials utilizing a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) have been shown to be safe and effective in inducing anti-tumor immune response in pancreatic adenocarcinoma patients. GVAX treated patients have demonstrated infiltration of PD-1+ T cells which is a major immunosuppressive mechanism in the tumor microenvironment. We hypothesized that the use of a PD-1 blocking antibody and GVAX will improve vaccine therapy and pancreatic cancer survival.

Methods: Mice were orthotopically transplanted with 2 x 106 Panc02 pancreatic tumor cells to form liver metastases by a hemisplenectomy technique on day 0. Following tumor transplantation, wild-type or PD-1 knockout mice were treated subcutaneously with a mouse GM-CSF secreting pancreatic tumor vaccine (mouse GVAX) in combination with anti-PD-1 antibodies or IgG isotype control. GVAX was given subcutaneously to mice on days 4, 7, 14, and 21 following tumor transplantation, together with a single low-dose of Cytoxan on day 3. Anti-PD-1 antibodies or IgG were administered twice weekly starting post-operative day 3.

Results: PD-1 knockout mice challenged with pancreatic liver metastases had a significant survival advantage over wild-type mice (p=0.0002). Wild-type mice showed improved survival both with anti-PD-1 antibody alone (p=0.008) or in combination with vaccine (p&lt;0.0001) versus IgG controls. GVAX in combination with anti-PD-1 antibodies versus anti-PD-1 antibodies alone shows a statistically significant improved survival (p&lt;0.05). Memory T cell analysis demonstrated a strong trend toward increased tumor infiltration of CD8+ effector memory T cells in the combinatorial treatment group versus vaccine alone (66.67% vs 26.47%, p= 0.1). Tumor antigen (mesothelin)-specific cytotoxic CD8+ tumor infiltrating lymphocytes were increased in the combination treatment group (GVAX and anti-PD1 therapy) versus GVAX alone (13.4% vs 5.29%).

Conclusions: PD-1 blockade through monoclonal antibodies or genetic knockout in combination with vaccine result in a synergistic anti-tumor effect in a preclinical model of pancreatic cancer versus treatment with anti-PD1 alone. Additionally, anti-PD1 treatment facilitates tumor infiltration of functionally activated mesothelin specific CD8+ T cells. Anti-PD-1 blockade antibody is currently being tested in phase II clinical trials for treating chemotherapy-refractory solid tumor patients. Our study provides a strong rationale for combining PD-1 antibody with GVAX therapy for pancreatic cancer treatment.

This abstract is also presented as Poster B28.

Citation Format: Kevin C. Soares, Kelly Olino, Barish Edil, Donger Zhou, Anthony Wamwea, Ashley Leubner, Richard Schulick, Drew Pardoll, Elizabeth Jaffee, Lei Zheng. Granulocyte macrophage colony stimulating factor (GM-CSF) pancreas tumor vaccine in combination with blockade of PD-1 in a preclinical model of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR9.