Abstract 2470: Harnessing cytomegalovirus immunity against pancreatic tumors for immunotherapy
Authors: Marrocco Remi , Patel Jay , Sun Siming , Medari Rithika , Gulay Kevin , Lucero-Meza Eduardo , Mose Evangeline , Lowy Andrew , Benedict Chris , de Mendoza Tatiana Hurtado 
Published: March 2024

Abstract
Immunotherapy has had very limited success in pancreatic cancer, due to its low mutational burden and immunosuppressive microenvironment. Our approach consists in redirecting pre-existing antiviral immunity against pancreatic tumors by delivering viral antigens using the tumor penetrating peptide iRGD .This peptide, targets the tumor vasculature through αv integrins and neuropilin-1, delivering conjugated or co-administered cargo to tumors. Here we used mouse cytomegalovirus (CMV) as an infection model. CMV is a β-herpesvirus that induces a strong T-cell response in mice and humans, comprising &gt;10% of all circulating CD4 and CD8 T cells mostly with effector-memory phenotype. Importantly, human CMV infects over 60% of the world’s population rendering it a suitable candidate for translation. Mice latently infected with CMV were orthotopically implanted with KPC pancreatic tumor cells and treated with systemic injections of vehicle or iRGD plus CMV class I and II binding peptides. Another cohort of age matched uninfected mice was used as a control. Tumor growth and mouse weight were monitored twice a week and CMV specific immune responses were measured in spleen and tumor by flow cytometry, using tetramer staining and CMV specific peptide recall. CMV infected mice receiving iRGD + CMV peptides responded to treatment as evidenced by delayed tumor growth associated with increased tumor necrosis and T cell infiltration. In addition, flow cytometry analysis of tumor and spleen showed a significant increase in CMV specific T cells that produced significant amounts of IFN-γ and TNF-α upon CMV peptide recall. Furthermore, tumor regulatory T cells (Treg) were significantly reduced and the CD8/T reg ratio was greatly increased. Survival studies showed a 68% increase in median survival in the treated and infected group. Combining this strategy with anti-PD1 and or anti-IL10R did not significantly improve the benefits of iRGD + CMV therapy alone. Other combinations with chemotherapy and TME remodeling agents are being tested.Taken together, this data shows we can deliver antigens to pancreatic tumors via iRGD and elicit an anti-tumor immune response that results in delayed tumor growth and has a survival benefit. This is a mutation agnostic approach with high translational value, since more than 60% of the population has previous CMV immunity and iRGD in combination with chemotherapy is already in phase II clinical trials for advanced pancreatic cancer.
Citation Format: Remi Marrocco, Jay Patel, Siming Sun, Rithika Medari, Kevin Gulay, Eduardo Lucero-Meza, Evangeline Mose, Andrew Lowy, Chris Benedict, Tatiana Hurtado de Mendoza. Harnessing cytomegalovirus immunity against pancreatic tumors for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2470.