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Therapeutic efficacy of an oncolytic influenza virus carrying an antibody against programmed cell death 1 in hepatocellular carcinoma.

Oncolytic virus (OV) therapy is a promising novel immunotherapy. In this report, we engineered a novel oncolytic influenza virus carrying an anti-human programmed cell death 1 (PD-1) monoclonal antibody utilizing reverse genetics. A reassortant chimeric influenza virus, named rFlu-huPD1, was synthesized as follows: the heavy chain of the PD-1 antibody was encoded on the PB1 fragment, and the light chain of the PD-1 antibody was encoded on the PA fragment. rFlu-huPD1 antibodies were produced in infected ovalantoic eggs and could replicate to high titers. Moreover, selective cytotoxicity of rFlu-huPD1 was upregulated in multiple hepatocellular carcinoma (HCC) cancer cell lines compared to a control, as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the activation of T cells in the spleen of tumor-bearing BALB/c mice treated with rFlu-huPD1 was observed, especially cytotoxic CD8+ T cell activation in vivo. Additionally, in a patient-derived xenograft (PDX) liver cancer mouse model, tumor growth was reduced and the overall survival of the mice was increased by intratumoral injections with rFlu-huPD1 compared with wild-type PR8 virus. Taken together, these findings provide evidence for the utility of a combination of oncolytic influenza viruses expressing PD-1 inhibitors for use in HCC virotherapy.