Concurrent expression of HP-NAP enhances antitumor efficacy of oncolytic vaccinia virus but not for Semliki Forest virus

Jing Ma,Chuan Jin,Matko Čančer,Hai Wang,Mohanraj Ramachandran,Di Yu

doi:10.1016/j.omto.2021.04.016

Abstract

Oncolytic viruses (OVs) represent promising therapeutic agents for cancer therapy by selective oncolysis and induction of anti-tumor immunity. OVs can be engineered to express tumor-associated antigens and immune-modulating agents to provoke stronger antitumor immunity. Here, we engineered vaccinia virus (VV) and Semliki Forest virus (SFV) to express neuroblastoma-associated antigen disialoganglioside (GD2) and the immune modulator Helicobacter pylori neutrophil-activating protein (NAP) and compared their therapeutic potency. Oncolytic VV did not exhibit any antitumor benefits, whereas SFV was able to delay subcutaneous neuroblastoma (NXS2) tumor growth. Additional expression of the GD2 mimotope (GD2m) by VV-GD2m or SFV-GD2m did not improve their anti-tumor capacity compared to the parent viruses. Further arming these OVs with NAP resulted in contrasting anti-tumor efficacy. VV (VV-GD2m-NAP) significantly improved therapeutic efficacy compared to VV-GD2m, which was also associated with a significantly elevated anti-GD2 antibody, whereas there was no additive antitumor efficacy for SFV-GD2m-NAP compared to SFV-GD2m, nor was the anti-GD2 antibody response improved. Instead, NAP induced higher neutralizing antibodies against SFV. These observations suggest that distinct immune stimulation profiles are elicited when the same immunostimulatory factor is expressed by different OVs. Therefore, careful consideration and detailed characterization are needed when engineering OVs with immune-modulators.

Highlights

Oncolytic viruses (OVs) are promising agents for cancer therapy due to their ability to selectively replicate in and destroy tumor cells while leaving the healthy cells unharmed
With the use of an NXS2 neuroblastoma tumor model, we demonstrate that arming neutrophilactivating protein (NAP) (SFV-GD2 mimotope (GD2m)-NAP) adds no improvement to oncolytic Semliki Forest virus (SFV) when compared with the non-modified SFV (SFV-GD2m), instead the anti-SFV antibody response was boosted by NAP
In Vaccinia virus (VV) constructs, the mimotope was fused with a Renilla luciferase (Rluc) and c-Myc tag, in the backbone of a tumor-selective VV-Deletion of TK (dTK), in which thymidine kinase (TK) has been deleted (Figure 1A)

Summary

Introduction

Oncolytic viruses (OVs) are promising agents for cancer therapy due to their ability to selectively replicate in and destroy tumor cells while leaving the healthy cells unharmed. A variety of viruses have been investigated as prospective cancer therapeutic agents, ranging from small RNA viruses to large DNA viruses.[1,2,3,4] The oncolysis of tumor cells can be immunogenic and can elicit an anti-tumor immune response, contributing to the OV therapeutic effects to a large extent.[2,5] Further enhancing the anti-tumor immune response is one way to improve its efficacy. Deletion of TK (dTK) renders the virus replication preferentially in dividing cells, which favors tumor targeting and selection.[15]

Methods

Results

Conclusion