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Updated: Jun 8, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Trabectedin promotes oncolytic virus antitumor efficacy, viral gene expression, and immune effector function in
Emily M Ringwalt1,2, Mark A Currier1, Andrea M Glaspell1
1Center for Childhood Cancer Research, Nationwide Children's Hospital, Columbus, OH 43215, USA.
Abstract:
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.
Insights
Trabectedin enhances oncolytic herpes simplex viroimmunotherapy by disrupting antiviral responses and reducing immunosuppressive cells. This combination therapy promotes immune-mediated tumor regression through direct viral killing and enhanced cytotoxic lymphocyte activity.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Trabectedin, a DNA alkylator, previously showed synergy with oncolytic viroimmunotherapy.
- The underlying mechanisms for this synergy were not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which trabectedin enhances oncolytic herpes simplex viroimmunotherapy.
- To evaluate the efficacy of trabectedin-enhanced viroimmunotherapy in syngeneic murine sarcoma models.
Main Methods:
- Investigated trabectedin's effect on cellular antiviral responses in human sarcoma cells.
- Assessed viral transcript levels post-trabectedin treatment.
- Evaluated tumor regression and immune cell infiltration in syngeneic murine sarcoma models treated with trabectedin and oncolytic virus.
Main Results:
- Trabectedin disrupts the intrinsic cellular antiviral response, increasing viral transcript presence.
- In murine models, trabectedin enhanced viroimmunotherapy by reducing immunosuppressive CD4 T and myeloid cells.
- Trabectedin stimulated granzyme expression in tumor-infiltrating T and natural killer cells, leading to immune-mediated regressions.
Conclusions:
- Trabectedin enhances oncolytic viroimmunotherapy through dual mechanisms: direct tumor cell killing and immune activation.
- These findings support the clinical translation of combining trabectedin with oncolytic herpes simplex virus therapy.
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