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

• Published in: Molecular therapy. Oncolytics Vol. 11; pp. 62 - 74
• Main Authors: Denton, Nicholas L., Chen, Chun-Yu, Hutzen, Brian, Currier, Mark A., Scott, Thomas, Nartker, Brooke, Leddon, Jennifer L., Wang, Pin-Yi, Srinivas, Rachelle, Cassady, Kevin A., Goins, William F., Cripe, Timothy P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.12.2018; Elsevier Limited; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Antitumor activity; Bisphosphonates; Cancer therapies; Cell activation; Clinical trials; Clodronic acid; Ewing sarcoma; Ewing's sarcoma; Ewings sarcoma; Gene expression; Genomics; Herpes simplex; Herpes viruses; Immunotherapy; Macrophages; Medical research; Metastases; Metastasis; myeloid-derived suppressor cells; Natural killer cells; Oncolysis; oncolytic herpes virus; pediatric sarcoma; Pediatrics; Solid tumors; Stroma; Suppressor cells; trabectedin; tumor-associated macrophage; Tumorigenesis; Tumors; Xenografts; United States > US; Ohio; Ewing sarcoma; trabectedin; oncolytic herpes virus; immunotherapy; tumor-associated macrophage; pediatric sarcoma; myeloid-derived suppressor cells
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2018.10.001

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.