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.
Authors
- Timothy P. Cripe (ORCID: https://orcid.org/0000-0002-8595-3577)
- Dean A. Lee (ORCID: https://orcid.org/0000-0001-6693-5392)
- Andrea M. Glaspell (ORCID: https://orcid.org/0000-0002-7035-9305)
- Emily Schwarz (ORCID: https://orcid.org/0000-0002-2817-9300)
- Maren Cam (ORCID: https://orcid.org/0000-0002-6337-6414)
- Louis Boon (ORCID: https://orcid.org/0000-0002-0937-9171)
- Ryan D. Roberts (ORCID: https://orcid.org/0000-0001-5028-744X)
- Matthew V. Cannon (ORCID: https://orcid.org/0000-0002-3035-9490)
- Amy C. Gross (ORCID: https://orcid.org/0000-0002-0123-5085)
- Mark A. Currier (ORCID: https://orcid.org/0000-0002-0064-2025)
- Emily M. Ringwalt (ORCID: https://orcid.org/0000-0001-8307-7887)
- Elaine R. Mardis (ORCID: https://orcid.org/0000-0002-5892-1553)
- William Edgar Carson (ORCID: https://orcid.org/0000-0001-7024-7533)
- Laura Biederman (ORCID: https://orcid.org/0000-0002-8877-7281)
- Pin-Yi Wang (ORCID: https://orcid.org/0000-0002-5420-2252)
- Prajwal Rajappa (ORCID: https://orcid.org/0000-0002-5911-9554)
- Matthew J. Gust (ORCID: https://orcid.org/0009-0009-3159-2559)
- Chun‐Yu Chen (ORCID: https://orcid.org/0000-0001-7199-3271)
Institutions
- Nationwide Children's Hospital (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- The Ohio State University Wexner Medical Center (US)
- Pure Biologics (Poland) (PL)
- The Ohio State University (US)
Publication Details
- Journal
- Molecular Therapy Oncology
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1016/j.omton.2024.200886
- Citations
- 8
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.40
Funders
- St. Baldrick's Foundation
- Nationwide Children's Hospital
- CancerFree KIDS
- Pelotonia
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- National Cancer Institute
- Moonshot Research and Development Program
- Cancer Moonshot