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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma
Yusuke Mochizuki1, Hiroshi Tazawa2,3, Koji Demiya1
1Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
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.
Insights
Oncolytic virotherapy with OBP-502 enhances PD-1 blockade efficacy in osteosarcoma. This combination therapy boosts antitumor immune responses, suggesting a promising new strategy for treating osteosarcoma patients refractory to PD-1 inhibitors.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Immune checkpoint inhibitors like anti-programmed cell death 1 (PD-1) antibodies have limited efficacy in osteosarcoma (OS).
- Oncolytic virotherapy offers a novel approach to enhance antitumor immune responses.
- A telomerase-specific oncolytic adenovirus, OBP-502, was developed for cancer treatment.
Purpose of the Study:
- To evaluate the combined therapeutic effect of PD-1 blockade and OBP-502 in osteosarcoma.
- To investigate the expression of key receptors and ligands involved in immune response in OS cells.
- To assess the impact of combination therapy on tumor-infiltrating CD8+ T cells.
Main Methods:
- Analysis of coxsackie and adenovirus receptor (CAR), integrins (αvβ3, αvβ5), and programmed cell death ligand 1 (PD-L1) expression in murine OS cells (K7M2, NHOS).
- Assessment of OBP-502 cytopathic activity using the XTT assay and immunogenic cell death markers (ATP, HMGB1).
- Evaluation of antitumor effects and CD8+ T cell infiltration in subcutaneous OS tumor models treated with combination therapy.
Main Results:
- K7M2 and NHOS cells exhibited high expression of integrins αvβ3 and αvβ5, but not CAR.
- OBP-502 significantly reduced OS cell viability, increased PD-L1 expression, and elevated extracellular ATP and HMGB1 levels.
- Combined OBP-502 and PD-1 blockade significantly enhanced antitumor efficacy and CD8+ T cell infiltration in vivo.
Conclusions:
- Telomerase-specific oncolytic virotherapy (OBP-502) shows potential as an immunogenic therapy for osteosarcoma.
- Combining OBP-502 with PD-1 blockade can overcome resistance to PD-1 inhibitors in osteosarcoma.
- This combination strategy represents a promising approach to augment antitumor immunity in osteosarcoma.
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