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

Zuqiang Liu,Z Sheng Guo,Roshni Ravindranathan,Pawel Kalinski,David L Bartlett

doi:10.1038/ncomms14754

Zuqiang Liu, Z Sheng Guo + Show 3 more

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https://doi.org/10.1038/ncomms14754

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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.

Highlights

Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients
It consists of active immunotherapy such as cancer vaccines[5], passive immunotherapy such as adoptive cell transfer, including ex vivo expanded tumour-infiltrating lymphocyte and CAR-T cells[6,7], and strategies to modulate the immunosuppressive tumour microenvironment (TME) such as using antibodies that bind to and modulate the function of immune checkpoints
It was reported that the expression of PD-1 is upregulated on exhausted CD8 þ T cells from mice chronically infected with lymphocytic choriomeningitis virus, and PD-1/PD-L1 blockade enhanced virus-specific CD8 þ T-cell responses and reduced viral load[21]

Summary

Introduction

Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. It was recognized that tumour cells express PD-L1 on their surface, inactivating immune effector cells Those tumours with high levels of PD-L1 on their surface and a lymphocytic infiltrate have been shown to respond well to anti-PD-1/anti-PD-L1 therapy, including melanoma, Hodgkin’s lymphoma, non-small-cell lung, bladder, gastric, renal and ovarian cancers[23]. In this regard, it is interesting to note the hints that virus-associated cancers respond at high rates to PD1 pathway blockade[8]. Our study tests a rational combination therapy of oncolytic vaccinia and PD-L1 blockade in animal tumour models, with the potential for improving immunotherapy in cancer patients, including those who have naturally low/no PD-L1-expressing tumours

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