Trabectedin promotes oncolytic virus antitumor efficacy, viral gene expression, and immune effector function in models of bone sarcoma

• Published in: Molecular Therapy: Oncology Vol. 32; no. 4; p. 200886
• Main Authors: Ringwalt, Emily M., Currier, Mark A., Glaspell, Andrea M., Chen, Chun-Yu, Cannon, Matthew V., Cam, Maren, Gross, Amy C., Gust, Matthew, Wang, Pin-Yi, Boon, Louis, Biederman, Laura E., Schwarz, Emily, Rajappa, Prajwal, Lee, Dean A., Mardis, Elaine R., Carson, William E., Roberts, Ryan D., Cripe, Timothy P.
• Format: Journal Article
• Language: English
• Published: American Society of Gene & Cell Therapy 19-12-2024; Elsevier
• Subjects: cancer immunotherapy; Ewing sarcoma; Original; osteosarcoma; synergy; trabectedin; viroimmunotherapy
• ISSN: 2950-3299; 2950-3299
• DOI: 10.1016/j.omton.2024.200886

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.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.