An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Oncolytic viruses activate anti-tumor T cell responses.
• PD-L1 upregulation on tumor and immune cells causes resistance to oncolytic immunotherapy.

Purpose of the Study:

• To engineer an oncolytic virus co-expressing a PD-L1 inhibitor and GM-CSF.
• To evaluate the efficacy of this engineered virus in overcoming PD-L1-mediated immunosuppression and activating systemic anti-tumor immunity.

Main Methods:

• Generation of an oncolytic virus engineered to secrete a PD-L1 inhibitor and GM-CSF.
• Intratumoral injection of the engineered virus in a tumor model.
• Assessment of PD-L1 inhibition, T cell responses, and tumor rejection.

Main Results:

• The engineered virus systemically inhibited PD-L1 on tumor and immune cells.
• Intratumoral injection overcame PD-L1-mediated immunosuppression during T cell priming and effector phases.
• Effective rejection of both injected and distant tumors was achieved through systemic neoantigen-specific T cell responses.

Conclusions:

• Engineered oncolytic viruses secreting PD-L1 inhibitors can activate potent, tumor-specific T cell responses.
• This approach offers a promising immunotherapy for cancer patients, including those resistant to PD-1/PD-L1 blockade.
• The engineered virus demonstrates potential as a personalized, in situ vaccination strategy against cancer.