Safety and feasibility of virus-specific T cells derived from umbilical cord blood in cord blood transplant recipients

Abstract

Adoptive transfer of virus-specific T cells (VSTs) has been shown to be safe and effective in stem cell transplant recipients. However, the lack of virus-experienced T cells in donor cord blood (CB) has prevented the development of ex vivo expanded donor-derived VSTs for recipients of this stem cell source. Here we evaluated the feasibility and safety of ex vivo expansion of CB T cells from the 20% fraction of the CB unit in pediatric patients receiving a single CB transplant (CBT). In 2 clinical trials conducted at 2 separate sites, we manufactured CB-derived multivirus-specific T cells (CB-VSTs) targeting Epstein-Barr virus (EBV), adenovirus, and cytomegalovirus (CMV) for 18 (86%) of 21 patients demonstrating feasibility. Manufacturing for 2 CB-VSTs failed to meet lot release because of insufficient cell recovery, and there was 1 sterility breach during separation of the frozen 20% fraction. Delayed engraftment was not observed in patients who received the remaining 80% fraction for the primary CBT. There was no grade 3 to 4 acute graft-versus-host disease (GVHD) associated with the infusion of CB-VSTs. None of the 7 patients who received CB-VSTs as prophylaxis developed end-organ disease from CMV, EBV, or adenovirus. In 7 patients receiving CB-VSTs for viral reactivation or infection, only 1 patient developed end-organ viral disease, which was in an immune privileged site (CMV retinitis) and occurred after steroid therapy for GVHD. Finally, we demonstrated the long-term persistence of adoptively transferred CB-VSTs using T-cell receptor-Vβ clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.

CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies

“…However, third party donors are now being used to create banks for off-the-shelf products for immediate use [78]. There is a theoretical concern about graft versus host disease due to HLA mismatches from third party products; however, the reported rate has been low so far in published studies [79][80][81][82][83][84]. Table 2 groups in the setting of randomized controlled trials.…”

“…These were not restored in the 5 patients who did not clear CMV. Abraham et al 2019 [ 83 ] Cord blood derived virus-specific T cells 14 Allo-SCT patients who received cells for prophylaxis and infection. 7 patients who received prophylaxis did not develop reactivation.…”

Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

“…Heslop et al showed that ex vivo expanded, donor-derived, EBV-specific, polyclonal T cells, expressing an effector memory phenotype, persisted for as long as 12.5 years post-infusion [49] and provided persistent activity against viral reactivation with no evidence of monoclonal outgrowth. Other groups also have demonstrated long-term presence of polyclonal, donor-derived, single-or multivirus-specific T cells after adoptive transfer [52,109] or stable remission over the years of patients with refractory PTLD receiving EBV-specific T cells [110]. Notably, even in third-party settings, off-the-shelf, partially HLA-matched VSTs persisted up to 12 weeks following infusion, offering durable benefits [86,87], or provided up to 12 months control of previously refractory CMV infections in the majority of treated patients [111].…”

Cellular Therapeutic Approaches to Cytomegalovirus Infection Following Allogeneic Stem Cell Transplantation

“…Eighteen out of twenty-one products were successfully manufactured for clinical use and administered products were shown to confer antiviral immunity and/or complement pharmacotherapies. Obstacles still remain in terms of manufacturing times and yield, which is currently being assessed in a follow up clinical trial (NCT03594981) (59).…”