Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

Abstract

Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Here we hypothesized that an oncolytic poxvirus would attract T cells into the tumour, and induce PD-L1 expression in cancer and immune cells, leading to more susceptible targets for anti-PD-L1 immunotherapy. Our results demonstrate in colon and ovarian cancer models that an oncolytic vaccinia virus attracts effector T cells and induces PD-L1 expression on both cancer and immune cells in the tumour. The dual therapy reduces PD-L1+ cells and facilitates non-redundant tumour infiltration of effector CD8+, CD4+ T cells, with increased IFN-γ, ICOS, granzyme B and perforin expression. Furthermore, the treatment reduces the virus-induced PD-L1+ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules-double-positive, severely exhausted PD-1+CD8+ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients.

PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

“…Interestingly, in contrast to our findings with NDV, no significant PD-L1 induction was seen in that study in response to reovirus alone, and the induction of PD-L1 was attributed to the action of tumor-infiltrating NK cells (47). A study of combined oncolytic vaccinia and PD-L1 blockade demonstrated synergistic efficacy against the virus-treated peritoneal tumors, and the efficacy of such therapy was dependent on both CD4 + and CD8 + cells (44). Recombinant HSV expressing IL-12 combined with PD-1 blockade in a glioma model revealed a dependency on CD4 + and CD8 + T cells as well as macrophages (49).…”

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…Recently, oncolytic vaccinia virus (OV) has been shown to also lead to induction of PD-L1 largely through IFNγ produced by immune cells recruited into tumor milieu in response to viral infection and its efficacy was improved by PD-L1 blockade. 51 It is plausible that part of this response was mediated by NK cells, since an increase in cytotoxic markers-such as IFNγ, granzyme B and perforin-was observed in the dual treatment group while depletion of either CD4 or CD8 T cells had only a partial effect on the efficacy of OV/PD-L1 combination. Clinical trial results from testing a combination of talimogene laherparepvec virus with another checkpoint inhibitor, anti-CTLA-4 also points at a potential role of NK cells in mediating the efficacy of this combination in treatment of melanoma, where enrichment of genes related to a burst of virus-specific NK cells was detected.…”

Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade

“…Mouse tumors are less necrotic than human tumors, and their small size makes delivery of virus or antibodies easier. The sequencing of virus and antibody administration is also likely to affect therapy, as described for oncolytic vaccinia virus (Liu et al, 2017; Rojas et al, 2015). Here, we mostly administered oHSV at the time of initial antibody treatment.…”