TY - JOUR
T1 - Safety and feasibility of virus-specific T cells derived from umbilical cord blood in cord blood transplant recipients
AU - Abraham, Allistair A.
AU - John, Tami D.
AU - Keller, Michael D.
AU - Russell N Cruz, C.
AU - Salem, Baheyeldin
AU - Roesch, Lauren
AU - Liu, Hao
AU - Hoq, Fahmida
AU - Grilley, Bambi J.
AU - Gee, Adrian P.
AU - Dave, Hema
AU - Jacobsohn, David A.
AU - Krance, Robert A.
AU - Shpall, Elizabeth J.
AU - Martinez, Caridad A.
AU - Hanley, Patrick J.
AU - Bollard, Catherine M.
N1 - Funding Information:
This work was supported by a Program Project grant from the National Institutes of Health, National Cancer Institute (P01 CA148600) (E.J.S. and C.M.B.), the Amy Strelzer Manazevit Program (P.J.H.), the American Society of Hematology/Robert Wood Johnson Harold Amos Medical faculty development program (A.A.A.), and the American Cancer Society (PF-13e046e01-LIB) (P.J.H.).
Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/7/23
Y1 - 2019/7/23
N2 - 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-Vb clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.
AB - 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-Vb clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.
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U2 - 10.1182/bloodadvances.2019000201
DO - 10.1182/bloodadvances.2019000201
M3 - Article
C2 - 31292125
AN - SCOPUS:85069650281
SN - 2473-9529
VL - 3
SP - 2057
EP - 2068
JO - Blood Advances
JF - Blood Advances
IS - 14
ER -