Oncolytic measles vaccines encoding PD-1 and PD-L1 checkpoint blocking antibodies to increase tumor-specific T cell...

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• PD-1/PD-L1 checkpoint blockade is successful in cancer immunotherapy but faces resistance in immune-excluded tumors.
• Oncolytic virotherapy can overcome resistance by promoting inflammation and immune cell infiltration.
• Combining these approaches may enhance anti-tumor immunity.

Purpose of the Study:

• To evaluate the combination of oncolytic measles vaccine (MV) vectors with PD-1/PD-L1 blockade for cancer immunotherapy.
• To assess the potential of MV vectors encoding anti-PD-1 or anti-PD-L1 antibodies in overcoming tumor resistance.
• To investigate the induction of durable anti-tumor immune memory by these novel therapeutic vectors.

Main Methods:

• Utilized the MC38cea mouse model for oncolytic measles virus (MV) therapy.
• Administered MV combined with anti-PD-1 therapy or MV vectors encoding anti-PD-1/PD-L1 antibodies.
• Analyzed tumor samples and draining lymph nodes for immune cell infiltration and cytokine profiles.
• Assessed anti-tumor immune memory through tumor rechallenge experiments.

Main Results:

• MV combined with PD-1/PD-L1 blockade demonstrated modest survival benefits.
• Treatment led to increased intratumoral T cell effector cytokines and a shift towards an effector memory phenotype.
• Significant IFN-γ recall responses were observed in mice achieving complete remission after treatment with MV encoding anti-PD-1 or anti-PD-L1.
• Novel MV vectors encoding pembrolizumab, nivolumab, and atezolizumab were generated and validated in vitro.

Conclusions:

• Oncolytic MV vectors combined with PD-1/PD-L1 blockade show potential for enhancing anti-tumor immunity.
• These vectors can remodel the tumor immune environment and induce effector T cell responses.
• The developed MV vectors hold promise for inducing and supporting durable anti-tumor immune memory, representing a novel therapeutic strategy.