Re-directing anti-CMV memory immunity against pancreatic tumors for immunotherapy 2486

Abstract Description Current immunotherapies rely on tumor-associated neoantigen, and the presence of T cells specific for those neoantigen. As such, solid malignancies like pancreatic cancer having low mutational burden and very immunosuppressive microenvironment do not respond to immunotherapy. An alternative approach is to harness pre-existing memory T cells and redirect them toward tumors. In this context, cytomegalovirus (CMV)-specific memory T cells are attractive targets, as (1) >80% of the world’s population is infected, (2) CMV-specific T cells show broad tissue distribution associated to a tissue-resident effector memory phenotype and (3) up to 10% of all circulating CD4 and CD8 T cells are CMV-specific. Mice were infected with murine-CMV (MCMV) and then orthotopically implanted with pancreatic tumor cells >2 months later when viral latency was established. Mice with primary tumors were then therapeutically treated intravenously with MCMV peptide epitopes specific for various known anti-MCMV CD8 and CD4 T cells. Our results show potent T cell reactivation, expansion, and tumor targeting, associated with decreased tumor burden and prolonged lifetime, without the need of intra-tumor peptides injections. MCMV-specific T cells were dominant in the tumor, producing IFNγ, perforin, and granzyme B, leading to increased tumor necrosis and caspase-3 activation. Overall, our results show that CMV-specific memory T cells can be redirected to control a normally immunosuppressive solid tumor. Funding Sources Supported by FFBW 001 and NIH/NCI 1R21CA286198 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)