Myelolytic Treatments Enhance Oncolytic Herpes Virotherapy in Models of Ewing Sarcoma by Modulating the Immune Microenvironment

Abstract

Ewing sarcoma is a highly aggressive cancer that promotes the infiltration and activation of pro-tumor M2-like macrophages. Oncolytic virotherapy that selectively infects and destroys cancer cells is a promising option for treating Ewing sarcoma. The effect of tumor macrophages on oncolytic virus therapy, however, is variable among solid tumors and is unknown in Ewing sarcoma. We tested the effects of macrophage reduction using liposomal clodronate (Clodrosome) and trabectedin on the antitumor efficacy of intratumoral oncolytic herpes simplex virus, rRp450, in two Ewing sarcoma xenograft models. Both agents enhanced antitumor efficacy without increasing virus replication. The most profound effects were in A673 with only a transient effect on response rates in TC71. Interestingly, A673 was more dependent than TC71 on macrophages for its tumorigenesis. We found Clodrosome and virus together induced expression of antitumorigenic genes and reduced expression of protumorigenic genes in both the tumor-associated macrophages and the overall tumor stroma. Trabectedin reduced intratumoral natural killer (NK) cells, myeloid-derived suppressor cells, and M2-like macrophages, and prevented their increase following virotherapy. Our data suggest that a combination of trabectedin and oncolytic herpes virotherapy warrants testing in the clinical setting.

Immunotherapy in Pediatric Solid Tumors—A Systematic Review

“…The investigators demonstrated that by targeting the TME with trabectedin, a currently approved chemotherapeutic, the M2 macrophage population was decreased, allowing for uninhibited viral infection by the rRp450 virus. They also showed that combining rRp450 with trabectedin in an in vivo xenograft model of Ewing sarcoma significantly decreased tumor volume and increased animal survival [15]. Such studies provide an avenue for future investigations in viral therapy.…”

PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

“…In addition, excessive modi cation of the virus skeleton reduces its infection ability, and therefore oncolytic function [30]. Thus, recent studies are focusing on "conditionally enhancing" the e cacy of oncolytic viruses through pharmacological agents [31].…”

Immunotherapies for pediatric cancer: current landscape and future perspectives

“…Similarly, macrophage reduction also enhanced antitumor efficacy following oncolytic virotherapy in xenograft models of Ewing sarcoma [147]. Both macrophages and stroma had an increase in antitumorigenic and decrease in pro-tumorigenic gene expression, along with a shift in the phenotype of TAMs to a more inflammatory state [147]. Recently, the plasminogen activator inhibitor (PAI-1) has been shown to promote macrophage infiltration and polarization towards a pro-tumorigenic "M2" phenotype through the p38MAPK/NF-κB/IL-6 axis [148].…”

“…Antitumor efficacy was further increased by concurrent inhibition of CSF-1R and PD-1, which was associated with enhanced T cell infiltration through myeloid cell-derived chemokines CXCL9, CXCL10, and CXCL11. Similarly, macrophage reduction also enhanced antitumor efficacy following oncolytic virotherapy in xenograft models of Ewing sarcoma [147]. Both macrophages and stroma had an increase in antitumorigenic and decrease in pro-tumorigenic gene expression, along with a shift in the phenotype of TAMs to a more inflammatory state [147].…”

“…Although growing evidence stresses the importance of macrophage modulation in immunotherapy, macrophage dependence could vary across tumor types. Even between two different xenograft models of Ewing sarcoma tested, only one was found to benefit from macrophage modulation while the other model showed marginal effect of the combination on antitumor efficacy compared with virotherapy alone [147]. Along these lines, in a recent characterization of the tumor microenvironment of diffuse intrinsic pontine glioma (DIPG), there was not a significant macrophage content in analyzed tumors [149].…”