TCR-transgenic T cells and YB-1-based oncolytic virotherapy improve survival in a preclinical Ewing sarcoma xenograft mouse model

Front Immunol. 2024 Jan 22:15:1330868. doi: 10.3389/fimmu.2024.1330868. eCollection 2024.

Abstract

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.

Keywords: Ewing sarcoma; TCR-transgenic T cells; combination immunotherapy; oncolytic virotherapy; pediatric sarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • CD8-Positive T-Lymphocytes / pathology
  • Child
  • Disease Models, Animal
  • Heterografts
  • Humans
  • Mice
  • Oncolytic Virotherapy*
  • Receptors, Antigen, T-Cell / genetics
  • Sarcoma, Ewing*
  • Transcription Factors

Substances

  • Receptors, Antigen, T-Cell
  • YB-1 protein, mouse
  • Transcription Factors

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. SJS and UT were funded by the Wilhelm Sander-Foundation (2018.072.1. and 2021.007.1.) and the Cura Placida Children’s Cancer Research Foundation (20210823). SJS and HG were supported by the KKF clinician-scientist program of the School of Medicine, Technical University of Munich, and furthermore SJS was funded by the BZKF Young Scientist Fellowship. AJvO. was funded by grants from the Technical University of Munich, School of Medicine, Program ‘Translational Medicine’. UT is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project number 501830041, the “Zukunft Gesundheit e.V.” and the Dr. Sepp and Hanne Sturm Memorial Foundation. UT and HG are funded by the Robert Pfleger Foundation. SB is funded by the St. Baldrick’s Foundation (Martha’s BEST Grant for all #663113) and the ‘Du musst kämpfen’ Wohltätigkeitsinitiative (Access to Systems Biology-Based Individualized Cell Therapies for Adolescents with Refractory Pediatric Cancer, AdoRe, #200310stb).