Abstract B055: Harnessing cytomegalovirus immunity against pancreatic tumors for immunotherapy
Authors: Marrocco Remi , Patel Jay , Medari Rithika , Sun Siming , Gulay Kevin , Martsinkovskiy Alexei , Brunel Simon , Lucero-Meza Eduardo , Mose Evangeline , Lowy Andrew , Benedict Chris , Hurtado de Mendoza Tatiana 
Published: September 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 av 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. Methods: 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, liver and tumor by flow cytometry, using tetramer staining and CMV specific peptide recall. Results: 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, liver and spleen showed a significant increase in CMV specific T cells preferentially in the tumor. Surprisingly, these T cells preferentially infiltrated tumors regardless of the use of iRGD for tumor targeting of CMV peptides. Survival studies showed a marked increase in median survival, reaching 42 days in the infected and treated group, compared to 25 days in the vehicle treated one. The survival benefit was very similar in the presence or absence of iRGD. Combining this strategy with anti- PD1 and or anti-IL10R did not significantly improve the benefits of CMV therapy alone. On the other hand, combination with low dose gemcitabine (5mg/kg) significantly improved tumor growth delay and survival in the combination compared to either therapy alone. The median survival reached 49 days in the combination, compared to 39 for gemcitabine or CMV therapy alone and 32 for vehicle.Conclusions: We have recently performed single cell RNA sequencing in tumors from infected and CMV peptide or vehicle treated mice and will analyze the transcriptional profile and TCR sequence of the tumor infiltrating T cells. Preliminary analysis of this data shows a massive T cell infiltration and an increase in dendritic cells and macrophages in infected and treated mice. Taken together, this data shows we can deliver antigens to pancreatic tumors 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.
Citation Format: Remi Marrocco, Jay Patel, Rithika Medari, Siming Sun, Kevin Gulay, Alexei Martsinkovskiy, Simon Brunel, 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 AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B055.