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

Allistair A. Abraham, Tami D. John, Michael D. Keller, C. Russell N. Cruz, Baheyeldin Salem, Lauren Roesch, Hao Liu, Fahmida Hoq, Bambi J. Grilley, Adrian P. Gee, Hema Dave, David A. Jacobsohn, Robert A. Krance, Elizabeth. J. Shpall, Caridad A. Martinez, Patrick J. Hanley and Catherine M. Bollard

Key Points

  • CB-VSTs can be feasibly generated and are safe.

  • CB-VSTs persist long term after infusion in CBT 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.

  • Submitted March 25, 2019.
  • Accepted June 3, 2019.
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