Viral Delivery of CAR Targets to Solid Tumors Enables Effective Cell Therapy

Area of Science:

• Oncology
• Immunotherapy
• Virology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows limited efficacy in solid tumors due to the absence of highly and selectively expressed surface antigens.
• Current CAR T-cell therapies often rely on endogenous tumor antigens, which can be heterogeneous or absent.
• A generalizable CAR T-cell therapy approach is needed to overcome these limitations in solid tumors.

Purpose of the Study:

• To develop a method for tumor-selective delivery of surface antigens using an oncolytic virus.
• To enable a generalizable CAR T-cell therapy applicable to various solid tumors.
• To enhance CAR T-cell activity against tumors with low or absent endogenous antigen expression.

Main Methods:

• Engineered a thymidine kinase-disrupted vaccinia virus for selective delivery of CD19 (a surface antigen) to malignant cells.
• Tested the efficacy of CD19-modified oncolytic virus combined with CD19 CAR T-cell therapy in vitro against two tumor types.
• Evaluated the combination therapy in an immunocompetent B16 melanoma mouse model.

Main Results:

• Demonstrated potentiation of CD19 CAR T-cell activity against tumor cells in vitro.
• The combination therapy markedly delayed tumor growth and improved median survival in the B16 melanoma model.
• CD19 delivery enhanced CAR T-cell activity against tumor cells with low cognate antigen expression.

Conclusions:

• Oncolytic virus-mediated tumor antigen delivery is a viable strategy to enhance CAR T-cell therapy for solid tumors.
• This approach can overcome the challenge of antigen deficiency and improve therapeutic outcomes.
• Engineering tumors to express target antigens represents a promising avenue for effective adoptive cell therapy.