Oncolytic VSV Primes Differential Responses to Immuno-oncology Therapy
| Autor: | Kathy Mulgrew, JoAnn Suzich, Hong Ji, Scott A. Hammond, Elizabeth J. Kelly, Ronald Herbst, Nicholas M. Durham, Noel R. Monks, Kelly McGlinchey |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment viruses Melanoma Experimental Gene Expression Virus Replication B7-H1 Antigen Mice 0302 clinical medicine T-Lymphocyte Subsets Transduction Genetic Neoplasms Drug Discovery Tumor Microenvironment Transgenes Oncolytic Virotherapy Antibodies Monoclonal Combined Modality Therapy Oncolytic Viruses Cell killing Vesicular stomatitis virus 030220 oncology & carcinogenesis Molecular Medicine Original Article Immunotherapy Genetic Vectors Biology Vesicular stomatitis Indiana virus Immunomodulation 03 medical and health sciences Immune system Genetics medicine Biomarkers Tumor Animals Humans Molecular Biology Pharmacology Tumor microenvironment Innate immune system Genetic Therapy Interferon-beta Receptors OX40 biology.organism_classification Xenograft Model Antitumor Assays Oncolytic virus Disease Models Animal 030104 developmental biology Viral replication Immunology Interferons |
| Zdroj: | Molecular therapy : the journal of the American Society of Gene Therapy. 25(8) |
| ISSN: | 1525-0024 |
| Popis: | Vesicular stomatitis virus encoding the IFNβ transgene (VSV-IFNβ) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno-oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFNβ. Here, we show that VSV-IFNβ exhibits multiple mechanisms of action, including direct cell killing, stimulation of an innate immune response, recruitment of CD8 T cells, and depletion of T regulatory cells. Moreover, VSV-IFNβ promotes the establishment of a CD8 T cell response to endogenous tumor antigens. Our data demonstrate a significant enhancement of anti-tumor function for VSV-IFNβ when combined with checkpoint inhibitors, but not OX40 agonists. While the addition of checkpoint inhibitors to VSV-IFNβ generated robust tumor growth inhibition, it resulted in no increase in viral replication, transgene expression, or immunophenotypic changes beyond treatment with VSV-IFNβ alone. We hypothesize that tumor-specific T cells generated by VSV-IFNβ retain activity due to a lack of immune exhaustion when checkpoint inhibitors were used. |
| Databáze: | OpenAIRE |
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