Adenovirus-mediated specific tumor tagging facilitates CAR-T therapy against antigen-mismatched solid tumors

Area of Science:

• Immunotherapy
• Oncolytic Virology
• Cancer Biology

Background:

• Chimeric antigen receptor T-cell (CAR-T) therapy shows promise but faces challenges in solid tumors, including antigen heterogeneity and the immunosuppressive tumor microenvironment.
• Developing strategies to improve CAR-T cell targeting and efficacy in solid tumors is crucial for advancing cancer immunotherapy.

Purpose of the Study:

• To develop a novel tumor-tagging system using adenoviruses (Ad) to enhance CAR-T cell recognition and efficacy against solid tumors.
• To evaluate the effectiveness of a universal oncolytic Ad-tagging system in combination with single-target CAR-T cells for treating antigenically mismatched solid tumors.

Main Methods:

• Constructed recombinant adenoviruses (Ad) expressing a CD19 tag under tumor-specific promoters for universal cancer cell labeling.
• Utilized AdC68-TMC-tCD19 for universal tag expression and to facilitate CAR-T cell immunological synapse formation.
• Developed a replicative oncolytic adenovirus, AdC68-Sur-E1A-TMC-tCD19, combining tumor tagging with oncolysis.

Main Results:

• AdC68-TMC-tCD19 mediated universal tag expression and functional synapse formation between CAR-T cells and cancer cells.
• In a premixed mice model, CAR-T infusion following Ad-tagging resulted in 91.78% tumor volume inhibition and complete survival.
• The oncolytic tagging system significantly diminished established tumors in vivo and prolonged mice survival.

Conclusions:

• The universal oncolytic Ad-tagging system effectively labels cancer cells, enhancing CAR-T cell therapy against solid tumors.
• This combined strategy offers a powerful approach to overcome antigen mismatch and the inhibitory microenvironment in solid tumor immunotherapy.