Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus

• Published in: British Journal of Cancer Vol. 130; no. 7; pp. 1187 - 1195
• Main Authors: Hashimoto, Masashi, Kuroda, Shinji, Kanaya, Nobuhiko, Kadowaki, Daisuke, Yoshida, Yusuke, Sakamoto, Masaki, Hamada, Yuki, Sugimoto, Ryoma, Yagi, Chiaki, Ohtani, Tomoko, Kumon, Kento, Kakiuchi, Yoshihiko, Yasui, Kazuya, Kikuchi, Satoru, Yoshida, Ryuichi, Tazawa, Hiroshi, Kagawa, Shunsuke, Yagi, Takahito, Urata, Yasuo, Fujiwara, Toshiyoshi
• Format: Journal Article
• Language: English
• Published: London Springer Science and Business Media LLC 20.04.2024; Nature Publishing Group UK; Nature Publishing Group
• Subjects: 631/250/251; 631/67/1059/2325; Adenosine Triphosphate; Adenoviridae - genetics; Adenoviridae - metabolism; Adenoviruses; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD8 antigen; Cell activation; Cell differentiation; Cell Line, Tumor; Drug Resistance; Effector cells; Epidemiology; Gemcitabine; Humans; Immunological memory; Immunostimulants; Long-term effects; Lymphocytes; Lymphocytes T; Macrophages; Memory cells; Mice; Molecular Medicine; Oncology; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses - genetics; Oncolytic Viruses - metabolism; p53 Protein; Paclitaxel; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - therapy; Telomerase; Telomerase - genetics; Telomerase - metabolism; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02583-0

Background Pancreatic cancer is an aggressive, immunologically “cold” tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). Methods We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). Results First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. Conclusion OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.