Targeted adenovirus-mediated transduction of human T cells in vitro and in vivo

Clinical success in T cell therapy has stimulated widespread efforts to increase safety and potency and to extend this technology to solid tumors. Yet progress in cell therapy remains restricted by the limited payload capacity, specificity of target cell transduction, and transgenic gene expression efficiency of applied viral vectors. This renders complex reprogramming or direct in vivo applications difficult. Here, we developed a synergistic combination of trimeric adapter constructs enabling T cell-directed transduction by the human adenoviral vector serotype C5 in vitro and in vivo. Rationally chosen binding partners showed receptor-specific transduction of otherwise non-susceptible human T cells by exploiting activation stimuli. This platform remains compatible with high-capacity vectors for up to 37 kb DNA delivery, increasing payload capacity and safety because of the removal of all viral genes. Together, these findings provide a tool for targeted delivery of large payloads in T cells as a potential avenue to overcome current limitations of T cell therapy.

Automated summary

Clinical success in T cell therapy has prompted efforts to improve safety and efficacy, and expand its use in solid tumors. However, limitations in viral vectors, such as limited payload capacity and specificity of transduction, hinder progress in cell therapy. This study developed a combination of adapter constructs for targeted transduction of human T cells by adenoviral vectors, overcoming these limitations and increasing payload capacity. These findings provide a potential avenue to overcome current limitations of T cell therapy.