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

Chimeric antigen receptor T (CAR-T) therapy faces at least two major obstacles in solid tumors, including to find specific antigen among the heterogeneous tumor mass and to overcome the inhibitory microenvironment. Developing novel strategies to overcome these difficulties has been the burning issue in immunotherapy. Here we came up with the concept of tagging cancer cells by tumor-targeting adenoviruses (Ad). We constructed recombinant Ads expressing CD19 tag driven by tumor-specific promoters, which could label antigenically different tumors for single anti-CD19 CAR-T recognition. One Ad, namely AdC68-TMC-tCD19 could mediate universal tag expression and functional immunological synapse formation between CAR-T and cancer cells. In premixed mice model, all tagged mice survived after CAR-T infusion and tumor volume were inhibited by 91.78%. Furthermore, we combined the tumor tagging ability with oncolysis and generated the replicative AdC68-Sur-E1A-TMC-tCD19. Oncolytic tagging system could diminish established tumors in vivo and prolong mice survival significantly. Therefore, we suggest the universal oncolytic Ad-tagging system in combination with single target CAR-T cells could be a powerful complement in immunotherapy against antigenically mismatched solid tumors.