Abstract 1087: Synergistic mechanisms against pediatric bone sarcoma models: Trabectedin enhances oncolytic virotherapy intratumoral spread and antitumor immune activation

Abstract Osteosarcoma and Ewing sarcoma are the most common pediatric bone malignancies and, despite decades of research, efforts to treat patients with advanced disease remain dismal. To address this inadequacy, we leverage oncolytic herpes simplex virotherapy as a double-edged attack against tumors through 1) tumor cell-specific lysis and 2) antitumor immune stimulation. However, previous trials of oncolytic herpes simplex virotherapy in pediatric sarcomas displayed limited responses, likely due to the observed presence of immunosuppressive monocytes and macrophages. To improve efficacy, we combined oncolytic herpes simplex virotherapy with trabectedin, an FDA-approved DNA-binding agent known to disrupt gene expression and deplete monocytes and macrophages. Surprisingly, we found that the efficacy of this combination far surpassed our predictions, inducing complete and partial regressions in multiple models of Ewing sarcoma and osteosarcoma. To explore potential mechanisms driving this high degree of synergy, we performed single cell RNA sequencing on tumors of mice treated with monotherapy or combination therapy. Interestingly, trabectedin synergized with the oncolytic virotherapy through two unexpected mechanisms. Our analysis revealed that trabectedin increased intratumoral oncolytic virus spread by disrupting expression of the intrinsic antiviral response in human Ewing sarcoma cells. Additionally, trabectedin not only reduced immunosuppressive macrophages but also stimulated cytotoxic granzyme expression in infiltrating T and NK cells in immunocompetent osteosarcoma models. These effector NK and T cells were necessary for the regressions of osteosarcoma allografts treated with trabectedin and oncolytic virotherapy. Thus, trabectedin enhanced both the oncolytic effect of herpes simplex virotherapy and the effector function of cytotoxic lymphocytes that become activated in response to the virus. The combination of trabectedin and oncolytic herpes simplex virotherapy offers the potential to unite these mechanisms against bone tumors to achieve better outcomes for children. Citation Format: Emily Ringwalt, Mark Currier, Andrea Glaspell, Matthew V. Cannon, Chun-Yu Chen, Amy C. Gross, Maren Cam, Pin-Yi Wang, Ryan D. Roberts, Timothy P. Cripe. Synergistic mechanisms against pediatric bone sarcoma models: Trabectedin enhances oncolytic virotherapy intratumoral spread and antitumor immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1087.