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

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2024年2月5日

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Masashi Hashimoto,
Shinji Kuroda,
Nobuhiko Kanaya,
Daisuke Kadowaki,
Yusuke Yoshida,
Masaki Sakamoto,
Yuki Hamada,
Ryoma Sugimoto,
Chiaki Yagi,
Tomoko Ohtani,
Kento Kumon,
Yoshihiko Kakiuchi,
Kazuya Yasui,
Satoru Kikuchi,
Ryuichi Yoshida,
Hiroshi Tazawa,
Shunsuke Kagawa,
Takahito Yagi,
Yasuo Urata,
Toshiyoshi Fujiwara

摘要

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.