Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade
| Autor: | Edward J. Roy, Sara E. Berkey, Enyong Dai, Stacy J. Kowalsky, Zuqiang Liu, Mathilde Feist, David L. Bartlett, Zong Sheng Guo, Roshni Ravindranathan, Congrong Ma |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Programmed Cell Death 1 Receptor efficacy CD8-Positive T-Lymphocytes superagonist chemistry.chemical_compound Mice 0302 clinical medicine Neoplasms Drug Discovery Medicine Interleukin-15 Oncolytic Virotherapy ELISPOT Combined Modality Therapy vaccinia virus 3. Good health Killer Cells Natural IL-15 Interleukin 15 Molecular Medicine Female Original Article immunotherapy Recombinant Fusion Proteins antitumor immunity Virus 03 medical and health sciences Interferon-gamma Interleukin-15 Receptor alpha Subunit Cell Line Tumor Genetics Animals Humans Molecular Biology oncolytic virus Pharmacology business.industry Immunotherapy immune checkpoint blockade medicine.disease Xenograft Model Antitumor Assays Immunity Innate oncolytic vicotherapy Oncolytic virus Blockade 030104 developmental biology chemistry Cancer research Vaccinia business Ovarian cancer 030215 immunology |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0024 |
| Popis: | Oncolytic immunotherapy is a promising novel therapeutic for cancer, and further preclinical studies may maximize its therapeutic efficacy. In this study, we construct a novel oncolytic vaccinia virus (VV) expressing a superagoinst IL-15, a fusion protein of IL-15 and IL-15Ralpha. This virus, named vvDD-IL15-Rα, possesses similar replication efficiency as the parental virus vvDD yet leads to significantly more regression of the disease and extends the survival of mice bearing MC38 colon or ID8 ovarian cancer. This novel virus elicits potent adaptive antitumor immunity as shown by ELISPOT assays for interferon-gamma-secreting CD8+ T cells and by the rejection of tumor implants upon re-challenge in the mice, which were previously cured by vvDD-IL15-Rα treatment. In vivo cell depletion assays with antibodies showed that this antitumor activity is highly dependent on CD8+ T cells but much less so on CD4+ T cells and NK cells. Finally, the combination of the oncolytic immunotherapy with anti-PD-1 antibody dramatically improves the therapeutic outcome compared to either anti-PD-1 alone or vvDD-IL15-Rα alone. These results demonstrate that the IL-15-IL-15Rα fusion protein-expressing OV elicits potent antitumor immunity, and rational combination with PD-1 blockade leads to dramatic tumor regression and prolongs the survival of mice bearing colon or ovarian cancers. |
| Databáze: | OpenAIRE |
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