Overcoming the immunosuppressive tumor microenvironment and localizing adoptive cell and checkpoint blockade therapies to solid tumors remain major impediments to successful cancer immunotherapy. Humans experience many viral infections. Once controlled, the host retains memory T-cells throughout the entire body to sense reinfection or recrudescence. Mouse models have demonstrated that when that same virus is reencountered, these T-cells sound an alarm that induces a local immunostimulatory environment that activates and recruits many arms of the immune system. We observed that, like healthy tissue, human tumors are commonly surveyed by memory T-cells specific for previously encountered viral infections. Antiviral T-cell immune surveillance of tumors was recapitulated in mouse cancer models. We tested and discovered that local delivery of adjuvant-free peptide, derived from previously encountered mouse viral infections, recapitulated the sensing and alarm T-cell function within the tumor: recruiting and activating both the innate and adaptive immune system. This approach induced intratumoral accumulation of granzyme B+ CD8+ T and NK cells, and activated dendritic cells within the tumor and subsequently within the tumor draining lymph node. In addition to stimulating the tumor microenvironment, preliminary data suggest activated antiviral T-cells directly killed peptide coated tumor cells. Viral peptide administration arrested rapidly growing and poorly immunogenic B16 melanomas in vivo and this treatment synergized with anti-PD-L1 checkpoint blockade to eliminate measurable tumors, and prevented recurrence in 34% of mice. Most cured mice rejected subsequent B16 tumor challenges at distant sites, indicating that effective systemic tumor-specific immunity was established. In support of the hypothesis that this approach could translate to human cancer immunotherapy, we found that viral peptide alarm therapy of freshly isolated human tumors drove similar immune activation to that observed in mice. This study demonstrates that natural and existing antiviral immunity can be repurposed to fight tumors without the need for adjuvant, vaccination, or personalized identification of immunogenic tumor neoantigens.
Citation Format: Pamela C. Rosato, Sathi Wijeyesinghe, J. Michael Stolley, Christine Nelson, Rachel L. Davis, Luke S. Manlove, Christopher A. Pennell, Bruce R. Blazar, Clark C. Chen, Melissa A. Geller, Vaiva Vezys, David Masopust. Repurposing antiviral T-cells to fight tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B182.