Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer.

Lily Francis,Magesh Sathaiah,Deepa Magge,Zuqiang Liu,Pawel Kalinski,Julie A Urban,Zong Sheng Guo,Roshni Ravindranathan,David L Bartlett

doi:10.18632/oncotarget.7907

Abstract

An oncolytic poxvirus such as vvDD-CXCL11 can generate potent systemic antitumor immunity as well as targeted oncolysis, yet the antitumor effect is limited probably due to limited homing to and suppressed activity of tumor-specific adaptive immune cells in the tumor microenvironment (TME). We reasoned that a chemokine modulating (CKM) drug cocktail, consisting of IFN-α, poly I:C, and a COX-2 inhibitor, may skew the chemokine (CK) and cytokine profile into a favorable one in the TME, and this pharmaceutical modulation would enhance both the trafficking into and function of antitumor immune cells in the TME, thus increasing therapeutic efficacy of the oncolytic virus. In this study we show for the first time in vivo that the CKM modulates the CK microenvironment but it does not modulate antitumor immunity by itself in a MC38 colon cancer model. Sequential treatment with the virus and then CKM results in the upregulation of Th1-attracting CKs and reduction of Treg-attracting CKs (CCL22 and CXCL12), concurrent with enhanced trafficking of tumor-specific CD8+ T cells and NK cells into the TME, thus resulting in the most significant antitumor activity and long term survival of tumor-bearing mice. This novel combined regimen, with the oncolytic virus (vvDD-CXCL11) inducing direct oncolysis and eliciting potent antitumor immunity, and the CKM inducing a favorable chemokine profile in the TME that promotes the trafficking and function of antitumor Tc1/Th1 and NK cells, may have great utility for oncolytic immunotherapy for cancer.

Highlights

Oncolytic virotherapy (OVT) has demonstrated significant promise in both preclinical studies and clinical trials [1], and correlative studies confirm that OVT is a new form of immunotherapy for cancer [2,3,4]
An oncolytic poxvirus such as vvDD-CXCL11 can generate potent systemic antitumor immunity as well as targeted oncolysis, yet the antitumor effect is limited probably due to limited homing to and suppressed activity of tumor-specific adaptive immune cells in the tumor microenvironment (TME)
Cancer cells infected by an oncolytic poxvirus undergo programmed necrosis and apoptosis with release of ATP, HMGB1 as well as immunogenic endoplasmic reticulum chaperone gp96, all danger signals to the innate immune system, making it a type of immunogenic cell death (ICD) [36,37,38,39]

Summary

Introduction

Oncolytic virotherapy (OVT) has demonstrated significant promise in both preclinical studies and clinical trials [1], and correlative studies confirm that OVT is a new form of immunotherapy for cancer [2,3,4]. In the last few years, more and more research groups have devoted their attention to vaccinia virus (VV) as an oncolytic virus (OV). This has been attributed to the unique properties of VV, especially its native tumor tropism, efficient cell-cell spread and high levels of transgene expression in tumor cells. Pexa-Vec (JX-594), a Wyeth strain oncolytic VV, which has minimal therapy-associated toxicities and demonstrated objective clinical responses in human cancer patients [5, 6]. We have previously demonstrated that the WR strain of oncolytic vaccinia virus vvDD, with dual deletions of viral genes encoding thymidine kinase (tk) and vaccinia growth factor (vgf), is a tumor-selective replicating and potent OV in animal models [7]. Combination strategies may further enhance both the efficacy and safety of this oncolytic virus [14, 15]

Methods

Results

Conclusion