The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma

Author:

Schober Sebastian Johannes1ORCID,Schoening Caroline1ORCID,Eck Jennifer1ORCID,Middendorf Charlotte1ORCID,Lutsch Julia1ORCID,Knoch Pia1ORCID,von Ofen Anna Josefine1ORCID,Gassmann Hendrik1ORCID,Thiede Melanie1ORCID,Hauer Julia1ORCID,Kolk Andreas2ORCID,Mantwill Klaus3ORCID,Gschwend Jürgen E.3ORCID,Burdach Stefan E.G.14ORCID,Nawroth Roman3ORCID,Thiel Uwe1ORCID,Holm Per Sonne23ORCID

Affiliation:

1. 1Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, Munich, Germany.

2. 2Department of Oral and Maxillofacial Surgery, Medical University Innsbruck, Innsbruck, Austria.

3. 3Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

4. 4Institute of Pathology, School of Medicine, Technical University of Munich, Munich Germany.

Abstract

Abstract Purpose: Ewing sarcoma (EwS) is a highly malignant pediatric tumor characterized by a non-T-cell-inflamed immune-evasive phenotype. When relapsed or metastasized, survival is poor, emphasizing the need for novel treatment strategies. Here, we analyze the novel combination approach using the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition to augment EwS immunogenicity. Experimental Design: In vitro, viral toxicity, replication, and immunogenicity were studied in several EwS cell lines. In vivo tumor xenograft models with transient humanization were applied to evaluate tumor control, viral replication, immunogenicity, and dynamics of innate as well as human T cells after treatment with XVir-N-31 combined with CDK4/6 inhibition. Furthermore, immunologic features of dendritic cell maturation and T-cell-stimulating capacities were assessed. Results: The combination approach significantly increased viral replication and oncolysis in vitro, induced HLA-I upregulation, and IFNγ-induced protein 10 expression and enhanced maturation of monocytic dendritic cells with superior capacities to stimulate tumor antigen-specific T cells. These findings were confirmed in vivo showing tumor infiltration by (i) monocytes with antigen-presenting capacities and M1 macrophage marker genes, (ii) TReg suppression in spite of adenovirus infection, (iii) superior engraftment, and (iv) tumor infiltration by human T cells. Consequently, survival was improved over controls with signs of an abscopal effect after combination treatment. Conclusions: The joint forces of the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition induce therapeutically relevant local and systemic antitumor effects. Innate as well as adaptive immunity against EwS is boosted in this preclinical setting, pointing toward high therapeutic potential in the clinic.

Funder

Wilhelm Sander-Stiftung

Deutsche Forschungsgemeinschaft

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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