Star-crossed Side Effects: Evaluating the Interplay between Toxicity and Efficacy in the Combination Treatment of Trabectedin with HSV1716 in Murine Osteosarcoma

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The Ohio State University

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Pediatric patients with solid tumors have unacceptably low cure rates, and immunotherapy, such as oncolytic virotherapy, provides great promise for treatment. However, there is a lack of knowledge regarding the immunosuppressive microenvironment of solid tumors, and how this microenvironment affects the efficacy of virotherapy and other cancer immunotherapies. Tumor-Associated Macrophages, TAMs, specifically, M-2 like macrophages, and Myeloid Derived Suppressor Cells, MDSCs, are two key targets for improving the efficacy of immunotherapies as both play roles in immunosuppression. As such, it is suspected that a combined treatment that both reduces myelolytic cells in the microenvironment while stimulating a pro-inflammatory response will increase cytotoxic immune infiltration in the tumor microenvironment. We have previously demonstrated that trabectedin, an FDA-approved chemotherapy drug, in combination with oncolytic HSV, oHSV, has shown to stimulate tumor regression in two Ewing sarcoma Patient Derived Xenograft, PDX, models10. Our proposed mechanism suggests that trabectedin targets tumor-associated M2-like macrophages, and both depletes their levels while also polarizing remaining macrophages to an M1-like macrophage, which can perform phagocytosis against the tumor. While two Ewing sarcoma PDX models have demonstrated tumor regression in response to this combined myelolytic-virotherapy, it is unknown if these effects are generalizable to other non-Ewing sarcoma pediatric models or syngeneic models. This thesis explores the use of a combination treatment of the oncolytic virus, HSV1716, with the chemotherapy agent, trabectedin, in murine osteosarcoma. Specifically, this thesis focuses on the interplay between the toxicity and efficacy of the combination therapy of HSV1716 and trabectedin.



Oncolytic Viruses, Chemotherapy, Toxicity