Enhancement of CD70-specific CAR T treatment by IFN-γ released from oHSV-1-infected glioblastoma.

ABSTRACT

Even with progressive combination treatments, the prognosis of patients with glioblastoma (GBM) remains extremely poor. OV is one of the new promising therapeutic strategies to treat human GBM. OVs stimulate immune cells to release cytokines such as IFN-γ during oncolysis, further improve tumor microenvironment (TME) and enhance therapeutic efficacy. IFN-γ plays vital role in the apoptosis of tumor cells and recruitment of tumor-infiltrating T cells. We hypothesized that oncolytic herpes simplex virus-1 (oHSV-1) enhanced the antitumor efficacy of novel CD70-specific chimeric antigen receptor (CAR) T cells by T cell infiltration and IFN-γ release. In this study, oHSV-1 has the potential to stimulate IFN-γ secretion of tumor cells rather than T cell secretion and lead to an increase of T cell activity, as well as CD70-specific CAR T cells can specifically recognize and kill tumor cells in vitro. Specifically, combinational therapy with CD70-specific CAR T and oHSV-1 promotes tumor degradation by enhancing pro-inflammatory circumstances and reducing anti-inflammatory factors in vitro. More importantly, combined therapy generated potent antitumor efficacy, increased the proportion of T cells and natural killer cells in TME, and reduced regulatory T cells and transformed growth factor-ß1 expression in orthotopic xenotransplanted animal model of GBM. In summary, we reveal that oHSV-1 enhance the therapeutic efficacy of CD70-spefific CAR T cells by intratumoral T cell infiltration and IFN-γ release, supporting the use of CAR T therapy in GBM therapeutic strategies.