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

• Published in: Blood advances 2017-11, Vol.1 (24), p.2193-2205
• Main Authors: Withers, Barbara, Blyth, Emily, Clancy, Leighton E., Yong, Agnes, Fraser, Chris, Burgess, Jane, Simms, Renee, Brown, Rebecca, Kliman, David, Dubosq, Ming-Celine, Bishop, David, Sutrave, Gaurav, Ma, Chun Kei Kris, Shaw, Peter J., Micklethwaite, Kenneth P., Gottlieb, David J.
• Format: Article
• Language: English
• Subjects: Clinical Trials and Observations
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2017010223

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 = 28), Epstein-Barr virus (n = 1), or adenovirus (n = 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo–expanded VSTs (total = 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-specific T-cell immunity rose significantly and coincided with a rise in CD8+ terminal effector cells. PD-1 expression was elevated on CD8+ 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 CD8+ effector T cells possibly facilitated by VST infusion. This trial was registered at www.clinicaltrials.gov as #NCT02779439 and www.anzctr.org.au as #ACTRN12613000603718. •Partially HLA-matched third-party CMV-specific T cells provide long-term viral control in HSCT patients with resistant CMV infection.•Viral control occurs in the setting of recovery of CD8+ terminally differentiated effector T cells.