Coated oncolytic viruses based "double strike" strategy triggering CD19 CAR-T therapy in gastrointestinal tumors.

Abstract

The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is limited by the scarcity of stable antigen targets. To enhance CAR-T cell immunotherapy for solid tumors, we developed an integrated system that simultaneously introduces a surface antigen target for CAR-T cells and remodels the immunosuppressive tumor immune microenvironment (TIME) using an oncolytic adenovirus (OVs). This system leverages B cell membrane-derived CD19 as an artificial antigen target on tumor cells and enables in situ production of an αCD3e-αEpCAM bispecific T cell engager (BiTEs), which further strengthens the binding and cytotoxicity of CD19 CAR-T cells to cancer cells. The "double strike" therapeutic potential of Epv@CMP, both alone and in combination with CD19 CAR-T cells, was evaluated in colorectal cancer (CRC) and gastric cancer (GC) models. We have designed a lentiviral delivery system (Epv@CMP) that combines the homologous tumor cell membrane with the B cell membrane. The lentivirus has been genetically modified to express the dual-specificity antibody (αCD3e-αEpCAM) in tumor cells (Epv), aiming to enhance the accumulation of the virus in tumors and the efficacy of immunotherapy. Epv@CMP demonstrated efficient tumor-specific delivery and robust viral replication in vivo, leading to tumor regression and immune activation. Successful CD19 target anchor was also confirmed. The combination of Epv@CMP with CD19 CAR-T cells potently eliminated tumors in mouse models. Collectively, Epv@CMP represents a novel synergistic strategy that integrates oncolytic virotherapy with CAR-T cell immunotherapy to achieve potent tumor eradication and immune activation.