Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody
| Autor: | Yasuo Urata, Satoru Kikuchi, Masashi Hashimoto, Nobuhiko Kanaya, Hiroyuki Mizuguchi, Kento Kumon, Shunsuke Kagawa, Tomoko Tsumura, Katsuyuki Aoyama, Tetsushi Kubota, Yoshihiko Kakiuchi, Masahiko Nishizaki, Shinji Kuroda, Toshiyoshi Fujiwara, Hiroshi Tazawa, Toshiaki Morihiro |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cytotoxicity
Immunologic Telomerase abscopal effect T-Lymphocytes Programmed Cell Death 1 Receptor combined immunotherapy Mice 0302 clinical medicine Antineoplastic Agents Immunological Neoplasms Drug Discovery Medicine programmed death-1 Oncolytic Virotherapy 0303 health sciences biology Abscopal effect Drug Synergism Combined Modality Therapy oncolytic adenovirus Oncolytic Viruses tumor infiltrating lymphocytes 030220 oncology & carcinogenesis Systemic administration Molecular Medicine Immunogenic cell death Original Article Antibody Oncolytic adenovirus Combination therapy Adenoviridae Immunomodulation 03 medical and health sciences Lymphocytes Tumor-Infiltrating Cell Line Tumor immunogenic cell death Genetics Animals Humans immune checkpoint Molecular Biology 030304 developmental biology Pharmacology business.industry CD8 Genetic Therapy Xenograft Model Antitumor Assays Oncolytic virus Disease Models Animal Cancer research biology.protein business |
| Zdroj: | Mol Ther |
| Popis: | The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs. |
| Databáze: | OpenAIRE |
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