Remodeling of the tumor microenvironment using an engineered oncolytic vaccinia virus improves PD-L1 inhibition outcomes.

Jiaying Lou,Hui Zeng,Yi Wu,Yang Liu,Lijuan Fang,Jialin Dong,Shibing Wang,Ruijun Xu

doi:10.1042/bsr20204186

Abstract

Immune checkpoint inhibitor (ICI) immunotherapies have vastly improved therapeutic outcomes for patients with certain cancer types, but these responses only manifest in a small percentage of all cancer patients. The goal of the present study was to improve checkpoint therapy efficacy by utilizing an engineered vaccinia virus to improve the trafficking of lymphocytes to the tumor, given that such lymphocyte trafficking is positively correlated with patient checkpoint inhibitor response rates. We developed an oncolytic vaccinia virus (OVV) platform expressing manganese superoxide dismutase (MnSOD) for use as both a monotherapy and together with anti-PD-L1. Intratumoral OVV-MnSOD injection in immunocompetent mice resulted in inflammation within poorly immunogenic tumors, thereby facilitating marked tumor regression. OVV-MnSOD administration together with anti-PD-L1 further improved antitumor therapy outcomes in models in which these monotherapy approaches were ineffective. Overall, our results emphasize the value of further studying these therapeutic approaches in patients with minimally or non-inflammatory tumors.

Highlights

The development of immune checkpoint inhibitor (ICI) immunotherapies including anti-programmed cell death-1 (PD-1)/programmed cell death-Ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) have significantly improved survival and clinical outcomes in a subset of patients with certain tumor types [1,2,3]
oncolytic vaccinia virus (OVV) and OVV-manganese superoxide dismutase (MnSOD) were used to infect A20 and EL4 lymphoma cells (MOI = 2) for 24 h, after which significant MnSOD expression was detectable in cells infected with OVV-MnSOD but not in cells infected with OVV or treated with PBS (Figure 1B)
We evaluated the impact of MnSOD expression on OVV viral replication in these two lymphoma cell lines

Summary

Introduction

The development of immune checkpoint inhibitor (ICI) immunotherapies including anti-programmed cell death-1 (PD-1)/PD-L1 and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) have significantly improved survival and clinical outcomes in a subset of patients with certain tumor types [1,2,3]. The use of tumor-specific oncolytic viruses (OVs) capable of replicating in the tumor microenvironment (TME) and killing tumor cells to release tumor-specific antigens has the potential to improve cancer treatment outcomes [7,8]. Such virus-induced tumor cell lysis can activate innate immune receptors owing to the concomitant release of damage-associated molecular patterns, thereby bolstering antitumor immune responses [9]. Talimogene laherparepvec (T-VEC) [10,11], which is a herpes simplex virus strain that was engineered to encode the immune adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF), was approved as a first-in-class OV in U.S.A. in 2015 to treat metastatic

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