Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Intratumoral oncolytic virus therapy is a promising cancer treatment strategy.
• Its efficacy in cancers resistant to virus-mediated lysis is not well understood.
• Bladder cancer shows suboptimal response rates to current immunotherapies.

Purpose of the Study:

• To investigate the immunogenic potential of Newcastle Disease Virus (NDV) in bladder cancer.
• To determine if NDV therapy is effective regardless of tumor cell sensitivity to lysis.
• To evaluate NDV in combination with immune checkpoint blockade.

Main Methods:

• Infection of human and mouse bladder cancer cells with NDV.
• Assessment of cell death, immune pathway activation, and molecule expression (MHC, PD-L1).
• In vivo studies using a syngeneic murine bladder cancer model with intratumoral NDV therapy and combination treatments.

Main Results:

• NDV infection induced immunogenic cell death and immune pathway activation in all tested bladder cancer cell lines.
• Upregulation of MHC and PD-L1 was observed, irrespective of lysis sensitivity.
• Intratumoral NDV increased immune infiltration and shifted T cell phenotype, improving tumor control and survival when combined with PD-1 or CTLA-4 blockade.

Conclusions:

• Intratumoral NDV therapy demonstrates immunogenic potential in bladder cancer, independent of virus-mediated lysis.
• Combination therapy with NDV and immune checkpoint inhibitors enhances anti-tumor immune responses and clinical outcomes.
• These findings support clinical trials of NDV combined with systemic immunomodulatory agents for various cancers.