Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody

• Published in: Molecular therapy Vol. 28; no. 3; pp. 794 - 804
• Main Authors: Kanaya, Nobuhiko, Kuroda, Shinji, Kakiuchi, Yoshihiko, Kumon, Kento, Tsumura, Tomoko, Hashimoto, Masashi, Morihiro, Toshiaki, Kubota, Tetsushi, Aoyama, Katsuyuki, Kikuchi, Satoru, Nishizaki, Masahiko, Kagawa, Shunsuke, Tazawa, Hiroshi, Mizuguchi, Hiroyuki, Urata, Yasuo, Fujiwara, Toshiyoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-03-2020; American Society of Gene & Cell Therapy
• Subjects: abscopal effect; Adenoviridae - genetics; Adenoviridae - immunology; Animals; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; CD8; Cell Line, Tumor; combined immunotherapy; Combined Modality Therapy; Cytotoxicity, Immunologic; Disease Models, Animal; Drug Synergism; Genetic Therapy - adverse effects; Genetic Therapy - methods; Humans; immune checkpoint; immunogenic cell death; Immunomodulation; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Mice; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; oncolytic adenovirus; Oncolytic Virotherapy - adverse effects; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Oncolytic Viruses - immunology; Original; Programmed Cell Death 1 Receptor - antagonists & inhibitors; programmed death-1; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Telomerase - immunology; tumor infiltrating lymphocytes; Xenograft Model Antitumor Assays; oncolytic adenovirus; combined immunotherapy; tumor infiltrating lymphocytes; CD8; immune checkpoint; immunogenic cell death; programmed death-1; abscopal effect
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2020.01.003

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.
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Kanaya and colleagues show that telomerase-specific oncolytic adenoviruses can facilitate cytotoxic T lymphocytes recruitment into tumor tissues through immunogenic cell death induction, leading to abscopal effects via activation of systemic antitumor immune responses, and combination therapy with anti-PD-1 antibody creates synergistic antitumor effects that even lead to tumor eradication.