Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen...

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Cancer research

Background:

• Pediatric solid tumors present challenges for oncolytic virotherapy (OV) due to inert immune microenvironments and low antigenicity.
• Herpes simplex virus (HSV) can suppress host gene expression, hindering conventional OV efficacy.
• Developing effective OV strategies for resistant tumors requires overcoming immune suppression and enhancing antigen presentation.

Purpose of the Study:

• To engineer a multimodal oncolytic herpes simplex virus (oHSV) expressing ephrin A2 (EphA2), a shared tumor-associated antigen (TAA).
• To evaluate the efficacy of the EphA2-expressing oHSV in enhancing immune-mediated antitumor activity against resistant tumors.
• To assess the impact of the modified oHSV on T-cell populations and antitumor immune responses.

Main Methods:

• Genotypic and phenotypic verification of the engineered oHSV.
• Testing the oHSV in oHSV-resistant orthotopic, flank, and T cell-deficient mouse models.
• Assessing the virus in an unrelated peripheral tumor model expressing the shared TAA and evaluating T-cell responses.

Main Results:

• Virus-based EphA2 expression induced robust acquired antitumor immune responses in resistant murine brain and peripheral tumor models.
• The multimodal oHSV improved survival in viroimmunotherapy-resistant tumors.
• Treated mice exhibited altered infiltrating and peripheral T-cell populations and developed EphA2-specific CD8 effector-like populations.

Conclusions:

• The flexible viral platform enhances immune recognition of shared TAAs, improving therapeutic responses.
• This approach is well-suited for treating low-mutational load tumors.
• The engineered oHSV offers a promising strategy for enhancing OV efficacy in challenging cancer types.