Oncolytic adenovirus H101 enhanced antitumor effects of PD-1 blockade by downregulating CD47 on tumor cells

Abstract

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade are standard of care for many patients with advanced or metastatic cancer. However, a majority of patients remain resistant to these treatments. It has been reported that local oncolytic viral infection of tumors is capable of overcoming systemic resistance to PD-1 blockade, and strongly suggest the combination therapy of virotherapy with PD-1 blockade to improve therapeutic efficacy in tumors that are refractory to checkpoint blockade. We investigate the antitumor effects of an E1B55KD deleted oncolytic adenovirus H101, in combination with a humanized anti-PD-1 monoclonal antibody Camrelizumab on cancer. Combination of H101 with Camrelizumab demonstrated more potent antitumor effects than monotherapy in immune system humanized NSG mice subcutaneous (S.C.) tumor model. Increased tumor infiltrating T cells including the total and IFN-γ-expressing CD8+ T cells in the combination treatment group were observed. H101 infection induced decreased expression of CD47 on cancer cells, thereby promoting macrophage to phagocytose cancer cells. With the activation of macrophage by H101, increased levels of cytokines including TNF, IL-12 and IFN-γ were observed when induced THP-1 cells were co-cultured with H101-treated cancer cells, which further induced increased expressions of IFN-γ in T cells. Eliminating the IL-12 by anti-IL-12 neutralizing antibodies abolished IFN-γ production from T cells, showing activation of macrophages by H101 induced oncolysis to promote IFN-γ secretion of T cells via IL-12. Meanwhile, infection with H101 induced upregulation of PD-L1 on YTS-1 cells. These results suggested that H101 works synergistically to enhance therapeutic efficacy of PD-1 blockade on cancer by suppressing CD47 signaling, which may promote phagocytose of macrophages to tumor cells and activate CD8+ T cells. Combination of H101 with PD-1 blockade would be a novel strategy for treating cancer.

YB-1-based oncolytic virotherapy in combination with CD47 blockade enhances phagocytosis of pediatric sarcoma cells

“…At the same time, we present data that AdWT induces CD47 to a lower extent than XVir-N-31, and additional CD47i does not increase phagocytosis. Thus far, only the adenoviral viral protein E1B55K in adenoviruses has been described to repress CD47 ( 40 CD47 surface expression was actually decreased after virus infection (41). In our hands, the induction of CD47 by XVir-N-31 was reproducible for all assessed cell lines at 48hpi, equivalent to one replication cycle.…”

“…Thus far, only the adenoviral viral protein E1B55K in adenoviruses has been described to repress CD47 ( 40 ), whereas Qiao et al. showed for H101, an E1B55K-deleted adenovirus, that CD47 surface expression was actually decreased after virus infection ( 41 ). In our hands, the induction of CD47 by XVir-N-31 was reproducible for all assessed cell lines at 48hpi, equivalent to one replication cycle.…”