Stem cell memory EBV-specific T cells control post-transplant lymphoproliferative disease and persist in vivo

Adoptive T cell therapy (ACT), the therapeutic transfer of defined T cell immunity to patients, offers great potential in the fight against different human diseases including difficult-to-treat viral infections but response rates are still suboptimal. Very early differentiated stem cell memory T cells (TSCM) have superior self-renewal, engraftment, persistence, and anti-cancer efficacy, but their potential for anti-viral ACT remains unknown. Here, we developed a clinically-scalable protocol for expanding Epstein-Barr virus (EBV)-specific TSCM-enriched T cells with high proportions of CD4+ T cells and broad EBV antigen coverage. These cells showed tumor control in a xenograft model of post-transplant lymphoproliferative disorder (PTLD) and were superior to previous ACT protocols in terms of tumor infiltration, in vivo proliferation, persistence, proportion of functional CD4+ T cells, and diversity of EBV antigen specificity. Thus, our new protocol may pave the way for the next generation of potent unmodified antigen-specific cell therapies for EBV-associated diseases, including tumors, and other indications.