ITOC2 – 027. Redirecting adenovirus-specific T cells by a tumour-specific T cell receptor for therapy of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma is highly resistant to conventional therapies and need alternative treatments. Oncolytic viruses are promising tools for the treatment for solid tumours but unfortunately trigger strong T cell immune responses against the applied virus. Here, we wanted to investigate whether antiviral cytotoxic T lymphocytes triggered by oncolytic virotherapy can be redirected with a tumour specific TCR for therapy of HCC in an immunocompetent C57BL/6 mouse model. First, virus-specific T cells were induced by intraperitoneal challenge with oncolytic Adenovirus in Thy1.1. mice and splenocytes were used to generate bispecific T cells by lentiviral transfer of the OT-1 receptor in adenovirus-specific T cells. Resulting bispecific T cells were adoptively transferred into Thy1.2 recipient mice bearing HCC tumours expressing OVA minimum epitopes. Prior to Adoptive transfer, mice were preconditioned with Cyclophosphamid and Treosulfan to achieve lymphoreduction. Tracking lentiviral encoded GFP and CD8 by FACS analysis, we showed establishment of transduced CD8 T cells in blood, spleen and tumour tissue. Finally we demonstrated that, compared with naive and immunized mock-transduced cohorts, the group which received Ad/OT-1 specific T cells showed significantly improved regression and long-term survival. Our findings suggest that virus-specific T cells induced by oncolytic virotherapy can be successfully redirected with a tumour specific TCR to address therapy-resistant HCC.