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

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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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Abbreviations

ATP:

Adenosine triphosphate

APC:

Allophycocyanin

CAR:

Coxsackie and adenovirus receptor

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DAMPs:

Damage-associated molecular patterns

HMGB1:

High mobility group box 1

hTERT:

Human telomerase reverse transcriptase

ICD:

Immunogenic cell death

ICI:

Immune checkpoint inhibitor

LC3:

Microtubule-associated protein 1 light chain 3

MFI:

Mean fluorescence intensity

MOI:

Multiplicity of infection

OS:

Osteosarcoma

PARP:

Poly (ADP-ribose) polymerase

PBS:

Phosphate buffered saline

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

PFU:

Plaque-forming units

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Acknowledgements

We would like to thank Takeshi Ieda, Tomoko Sueishi, Yuko Hoshijima, and Tae Yamanishi for their excellent technical support.

Funding

This study was supported in part by grants from the Ministry of Education, Science, and Culture, Japan (to T. Fujiwara, Nos. 16H05416 and 19H03731; T. Ozaki, No. 25293323; T. Kunisada, No. 16K10862; K. Sugiu, No. 15K10446; T. Komatsubara, No. 18K15242; H. Tazawa, No. 16K10596; Y. Mochizuki, No. 19K16835).

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Authors and Affiliations

  1. Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Yusuke Mochizuki, Koji Demiya, Miho Kure, Hiroya Kondo, Tadashi Komatsubara, Kazuhisa Sugiu, Aki Yoshida & Toshifumi Ozaki

  2. Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Hiroshi Tazawa, Shunsuke Kagawa & Toshiyoshi Fujiwara

  3. Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Hiroshi Tazawa

  4. Sports Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, 700-8558, Japan

    Joe Hasei

  5. Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Toshiyuki Kunisada

  6. Oncolys BioPharma, Inc, Tokyo, 105-0001, Japan

    Yasuo Urata

  7. Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, 700-8558, Japan

    Shunsuke Kagawa

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  1. Yusuke Mochizuki
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  2. Hiroshi Tazawa
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Contributions

Conception and design: HT, TO, and TF. Development of methodology: YM, HT, KD, and JH. Acquisition of data (provided animals, provided facilities, etc.): YM, KD, MK, HK, TK, KS, and AY. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, and computational analysis): YM, HT, KD, and JH. Writing, review, and/or revision of the manuscript: YM, HT, and TF. Administrative, technical, or material support: YU. Study supervision: HT, TK, SK, TO, and TF.

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Correspondence to Hiroshi Tazawa.

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Conflict of interest

Y. Urata is President & CEO of Oncolys BioPharma, Inc. H. Tazawa and T. Fujiwara are consultants of Oncolys BioPharma, Inc. The other authors disclosed no potential conflicts of interest.

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Mochizuki, Y., Tazawa, H., Demiya, K. et al. Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma. Cancer Immunol Immunother 70, 1405–1417 (2021). https://doi.org/10.1007/s00262-020-02774-7

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