Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma
We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients. Overall design: We demonstrated the efficacy of oncolytic herpes simplex virotherapy (oHSV) and trabectedin in numerous preclinical human xenograft and mouse models of Ewing sarcoma and osteosarcoma. To characterize the mechanisms behind the synergy we observed, we analyzed oHSV presence, enriched pathways, and the cellular infiltrates in Ewing sarcoma and osteosarcoma tumors from treated mice using single-cell RNA transcriptomics. We tested the reliance of the combinatorial synergy in the Ewing sarcoma and osteosarcoma models on the infiltrating immune effector cells through natural killer cell and T cell depletions. Our work was funded by the NIH/NCI through U54 CA232561-01A1 for the Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center as well as F31 CA278353 and T32 CA269052.