Prophylactic antigen‐specific T‐cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant
David Gottlieb, Leighton Clancy, Barbara Withers, Helen M. McGuire, Fabio Luciani, Mandeep Singh, Brendan Hughes, Brian Gloss, David Kliman, Chun Kei Kris, Shyam Panicker, David Bishop, Ming‐Celine Dubosq, Ziduo Li, Selmir Avdic, Kenneth Micklethwaite, Emily Blyth
Abstract
Abstract Objectives Adoptive immunotherapy using donor‐derived antigen‐specific T‐cells can prevent and treat infection after allogeneic haemopoietic stem cell transplant (HSCT). Methods We treated 11 patients with a prophylactic infusion of 2 × 10 7 cells per square metre donor‐derived T‐cells targeting seven infections (six viral and one fungal) following HSCT. Targeted pathogens were cytomegalovirus (CMV), Epstein–Barr virus (EBV), adenovirus, varicella zoster virus, influenza, BK virus (BKV) and Aspergillus fumigatus . Results T‐cell products were successfully generated in all patients with 10 products responsive to 6 or 7 infections. T‐cell infusions were associated with increases in antigen‐experienced activated CD8 + T‐cells by day 30. CMV, EBV and BKV reactivation occurred in the majority of patients and was well controlled except where glucocorticoids were administered soon after T‐cell infusion. Three patients in that circumstance developed CMV tissue infection. No patient required treatment for invasive fungal infection. The most common CMV and EBV TCR clonotypes in the infusion product became the most common clonotypes seen at day 30 post‐T‐cell infusion. Donors and their recipients were recruited to the study prior to transplant. Grade III/IV graft‐versus‐host disease developed in four patients. At a median follow‐up of 390 days post‐transplant, six patients had died, 5 of relapse, and 1 of multi‐organ failure. Infection did not contribute to death in any patient. Conclusion Rapid reconstitution of immunity to a broad range of viral and fungal infections can be achieved using a multi‐pathogen‐specific T‐cell product. The development of GVHD after T‐cell infusion suggests that infection‐specific T‐cell therapy after allogeneic stem cell transplant should be combined with other strategies to reduce graft‐versus‐host disease.