Abstract B093: Cytomegalovirus immunotherapy: A mutation agnostic approach for pancreatic cancer treatment
Philip Salu, Catarina Maia, Remi Marrocco, Jay Patel, Rithika Medari, Eduardo Lucero-Meza, Simon Brunel, Alexei Martsinkovskiy, Siming Sun, Kevin Gulay, Malak Jaljuli, Evangeline Mose, Andrew Lowy, Chris Benedict, Tatiana Hurtado de MendozaAbstract
Background:
Immunotherapy has had limited success in pancreatic cancer, largely due to a low mutational burden and immunosuppressive microenvironment. Here we hypothesized that systemic delivery of viral antigens can redirect pre-existing antiviral immunity against pancreatic tumors in mice. Cytomegalovirus (CMV) was chosen, as it induces an extremely large/broad memory T- cell response and is very prevalent in the population.
Methods:
Mice latently infected with murine CMV (MCMV) were orthotopically implanted with pancreatic cancer cells and treated with systemic injections of MCMV CD8 and CD4 T cell epitopes. Tumor growth was monitored by ultrasound two times a week, and immune cell infiltration was analyzed by histology, flow cytometry and single- cell RNA sequencing (scRNA- seq). Statistical analysis was performed by two-way analysis of variance with Sidak correction. Humanized mouse models are developed using CMV+ patient derived pancreatic tumors and autologous PBMCs. Therapy is personalized for each patient based on their HLA and empirical testing of the human CMV peptides their T cells are most reactive to.
Results:
MCMV peptide therapy (MCMVp) promoted preferential accumulation of MCMV- specific T cells within pancreatic tumors, delaying tumor growth and increasing survival. Immunophenotyping and scRNA-seq analyses showed these T cells were highly activated and cytotoxic, leading to increased tumor necrosis and caspase- 3 activation. Depletion of CD4 and CD8 T cells abolished the impact of MCMVp therapy, indicating the antitumor response is T- cell dependent. CMV replication is strictly species specific. We recently performed studies identifying >200 new HCMV T cell epitopes increasing those known by ∼10-fold. In In the next steps towards clinical translation we are characterizing their HLA binding-specificity and testing their anti-tumor potential in humanized mouse models and patient derived tumor organoids co-cultured with autologous peripheral blood T cells.
Conclusions:
Our studies reveal that CMV- specific viral memory T cells can be re- directed to control a solid tumor normally refractory to immunotherapy. This is a mutation- agnostic approach with significant potential for the development of “off- the- shelf” therapeutics by stimulating pre-existing antiviral memory and it is widely applicable due to the high prevalence of CMV.
Citation Format:
Philip Salu, Catarina Maia, Remi Marrocco, Jay Patel, Rithika Medari, Eduardo Lucero-Meza, Simon Brunel, Alexei Martsinkovskiy, Siming Sun, Kevin Gulay, Malak Jaljuli, Evangeline Mose, Andrew Lowy, Chris Benedict, Tatiana Hurtado de Mendoza. Cytomegalovirus immunotherapy: A mutation agnostic approach for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B093.