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Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma.

Authors
  • Mochizuki, Yusuke1
  • Tazawa, Hiroshi2, 3
  • Demiya, Koji1
  • Kure, Miho1
  • Kondo, Hiroya1
  • Komatsubara, Tadashi1
  • Sugiu, Kazuhisa1
  • Hasei, Joe4
  • Yoshida, Aki1
  • Kunisada, Toshiyuki5
  • Urata, Yasuo6
  • Kagawa, Shunsuke7, 8
  • Ozaki, Toshifumi1
  • Fujiwara, Toshiyoshi7
  • 1 Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan. , (Japan)
  • 2 Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan. [email protected] , (Japan)
  • 3 Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. [email protected] , (Japan)
  • 4 Sports Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, 700-8558, Japan. , (Japan)
  • 5 Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan. , (Japan)
  • 6 Oncolys BioPharma, Inc, Tokyo, 105-0001, Japan. , (Japan)
  • 7 Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan. , (Japan)
  • 8 Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, 700-8558, Japan. , (Japan)
Type
Published Article
Journal
Cancer Immunology Immunotherapy
Publisher
Springer-Verlag
Publication Date
May 01, 2021
Volume
70
Issue
5
Pages
1405–1417
Identifiers
DOI: 10.1007/s00262-020-02774-7
PMID: 33151368
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvβ3 and αvβ5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvβ3 and αvβ5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+ T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

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