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Updated: Jul 4, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
TCR-transgenic T cells and YB-1-based oncolytic virotherapy improve survival in a preclinical Ewing sarcoma xenograft
Sebastian J Schober1, Melanie Thiede1, Hendrik Gassmann1
1Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
Background:
Ewing sarcoma (EwS) is an aggressive and highly metastatic bone and soft tissue tumor in pediatric patients and young adults. Cure rates are low when patients present with metastatic or relapsed disease. Therefore, innovative therapy approaches are urgently needed. Cellular- and oncolytic virus-based immunotherapies are on the rise for solid cancers.
Methods:
Here, we assess the combination of EwS tumor-associated antigen CHM1319-specific TCR-transgenic CD8+ T cells and the YB-1-driven (i.e. E1A13S-deleted) oncolytic adenovirus XVir-N-31 in vitro and in a xenograft mouse model for antitumor activity and immunostimulatory properties.
Results:
In vitro both approaches specifically kill EwS cell lines in a synergistic manner over controls. This effect was confirmed in vivo, with increased survival using the combination therapy. Further in vitro analyses of immunogenic cell death and antigen presentation confirmed immunostimulatory properties of virus-infected EwS tumor cells. As dendritic cell maturation was also increased by XVir-N-31, we observed superior proliferation of CHM1319-specific TCR-transgenic CD8+ T cells only in virus-tested conditions, emphasizing the superior immune-activating potential of XVir-N-31.
Conclusion:
Our data prove synergistic antitumor effects in vitro and superior tumor control in a preclinical xenograft setting. Combination strategies of EwS-redirected T cells and YB-1-driven virotherapy are a highly promising immunotherapeutic approach for EwS and warrant further evaluation in a clinical setting.
Insights
Combining T-cell therapy with oncolytic virus therapy shows synergistic effects against Ewing sarcoma (EwS). This innovative approach enhances antitumor activity and survival in preclinical models, offering new hope for metastatic EwS treatment.
Area of Science:
- Immunotherapy
- Oncolytic Virus Therapy
- Cancer Research
Background:
- Ewing sarcoma (EwS) is a rare, aggressive bone and soft tissue cancer primarily affecting pediatric and young adult patients.
- Metastatic or relapsed EwS has poor cure rates, necessitating novel therapeutic strategies.
- Cellular and oncolytic virus-based immunotherapies are emerging as promising treatments for solid tumors.
Purpose of the Study:
- To evaluate the combined antitumor activity and immunostimulatory properties of CHM1319-specific TCR-transgenic CD8+ T cells and the YB-1-driven oncolytic adenovirus XVir-N-31.
- To assess the efficacy of this combination therapy both *in vitro* and in a preclinical xenograft mouse model.
Main Methods:
- Assessment of synergistic killing of EwS cell lines by T cells and oncolytic adenovirus *in vitro*.
- Evaluation of *in vivo* antitumor activity and survival in a xenograft mouse model.
- Analysis of immunogenic cell death, antigen presentation, and dendritic cell maturation induced by virus infection.
Main Results:
- The combination therapy demonstrated synergistic killing of EwS cell lines *in vitro* and significantly increased survival *in vivo*.
- Virus-infected EwS tumor cells exhibited immunostimulatory properties, including enhanced immunogenic cell death and antigen presentation.
- Oncolytic adenovirus XVir-N-31 promoted dendritic cell maturation, leading to superior proliferation of specific T cells.
Conclusions:
- The combination of EwS-redirected T cells and YB-1-driven oncolytic virotherapy exhibits synergistic antitumor effects.
- This combination strategy shows superior tumor control in preclinical models and represents a highly promising immunotherapeutic approach for EwS.
- Further clinical evaluation of this combination therapy for Ewing sarcoma is warranted.
