Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells

Donor-derived adoptive T-cell therapy is a safe and effective treatment of viral infection posttransplant, but it is limited by donor serostatus and availability and by its personalized nature. Off-the-shelf, third-party virus-specific T cells ( VSTs) appear promising, but the long-term safety and durability of responses have yet to be established. We conducted a prospective study of 30 allogeneic hemopoietic stem cell transplant ( HSCT) patients with persistent or recurrent cytomegalovirus ( CMV) ( n = 5 28), Epstein-Barr virus ( n = 5 1), or adenovirus ( n = 5 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo-expanded VSTs ( total 5 50 infusions) at a median of 75 days post-HSCT ( range, 37 to 349 days). Safety, viral dynamics, and immune recovery were monitored for 12 months. Infusions were safe and well tolerated. Acute graft versus host disease occurred in 2 patients, despite a median HLA match between VSTs and the recipient of 2 of 6 antigens. At 12 months, the cumulative incidence of overall response was 93%. Virological control was durable in the majority of patients; the reintroduction of antiviral therapy after the final infusion occurred in 5 patients. CMV-specificT-cell immunity rose significantly and coincided with a rise in CD81 terminal effector cells. PD-1 expression was elevated on CD81 lymphocytes before the administration of third-party T cells and remained elevated at the time of viral control. Third-party VSTs show prolonged benefit, with virological control achieved in association with the recovery of CD81 effector T cells possibly facilitated by VST infusion.