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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
P53-Armed Oncolytic Virotherapy Promotes the Efficacy of PD1 Blockade in Murine Osteosarcoma Tumors
Miho Kure1, Hiroshi Tazawa2,3, Koji Demiya1
1Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Background/Aim:
Osteosarcoma (OS) is refractory to immune checkpoint inhibitors targeting programmed cell death 1 (PD1)/PD ligand 1 (PD-L1) due to poor immune response. We previously developed telomerase-specific, replication-competent oncolytic adenoviruses non-armed OBP-301 and P53-armed OBP-702 that exert antitumor efficacy against human OS cells. Recently, we demonstrated that P53-armed OBP-702 induces more profound immunogenic cell death and antitumor immune response against human and murine OS cells than does non-armed OBP-301. In the present study, we assessed the combined efficacy of PD1 blockade and P53-armed OBP-702 against murine OS cells.
Materials And Methods:
Three murine OS cell lines (K7M2, NHOS, NHOS-LM4) were used to assess the cytopathic effect of non-armed OBP-301 and P53-armed OBP-702 by XTT assay. Virus-induced immunogenic cell death was assessed by analyzing the levels of extracellular adenosine triphosphate and high-mobility group box protein B1. The expression of PD-L1 and PD-L2 was analyzed by flow cytometry. The malignant potential of NHOS-LM4 cells was analyzed by a migration and invasion assay. An orthotopic NHOS-LM4 tumor model was used to evaluate the antitumor efficacy of combination therapy with P53-armed OBP-702 and anti-PD1.
Results:
P53-armed OBP-702 exhibited antitumor potential for the induction of immunogenic cell death, apoptosis, autophagy, and PD-L1/2 upregulation in K7M2 and NHOS cells. NHOS-LM4 cells showed increased migratory and invasive ability compared to NHOS cells. P53-armed OBP-702 significantly suppressed the malignant potential of NHOS-LM4 cells. Combination dosing showed that P53-armed OBP-702 significantly promoted the antitumor effect of PD1 blockade against NHOS-LM4 tumors.
Conclusion:
Our results suggest that P53-armed OBP-702 is a promising agent for improving the antitumor effect of PD1 blockade in treating invasive OS.
Insights
P53-armed oncolytic adenovirus (OBP-702) enhances programmed cell death 1 (PD1) blockade efficacy against invasive osteosarcoma (OS). This combination therapy shows promise for improving antitumor immune responses in OS patients.
Area of Science:
- Oncology
- Virology
- Immunotherapy
Background:
- Osteosarcoma (OS) is often resistant to immune checkpoint inhibitors like PD1/PD-L1 blockade due to a weak immune response.
- Oncolytic adenoviruses, including P53-armed OBP-702, demonstrate antitumor activity and can induce immunogenic cell death in OS cells.
- P53-armed OBP-702 shows greater immunogenic cell death induction than non-armed OBP-301 in OS models.
Purpose of the Study:
- To evaluate the combined efficacy of P53-armed OBP-702 and PD1 blockade against murine osteosarcoma.
- To assess the impact of this combination therapy on tumor growth and immune response in an orthotopic OS model.
Main Methods:
- Assessed cytopathic effects and immunogenic cell death induction (ATP, HMGB1 release) of OBP-301 and OBP-702 in murine OS cell lines (K7M2, NHOS, NHOS-LM4).
- Analyzed PD-L1/PD-L2 expression via flow cytometry and evaluated migratory/invasive potential of NHOS-LM4 cells.
- Tested the antitumor efficacy of combination therapy (OBP-702 + anti-PD1) in an orthotopic NHOS-LM4 tumor model.
Main Results:
- P53-armed OBP-702 induced immunogenic cell death, apoptosis, autophagy, and upregulated PD-L1/2 in K7M2 and NHOS cells.
- NHOS-LM4 cells exhibited increased malignancy, but OBP-702 suppressed their invasive potential.
- Combination therapy significantly enhanced the antitumor effect of PD1 blockade in the NHOS-LM4 tumor model.
Conclusions:
- P53-armed OBP-702 demonstrates potential as an agent to augment PD1 blockade therapy for invasive osteosarcoma.
- The combination approach shows promise for overcoming resistance to PD1 blockade in OS treatment.
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