Production and first-in-man use of T cells engineered to express a HSVTK-CD34 sort-suicide gene
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Production and first-in-man use of T cells engineered to express a HSVTK-CD34 sort-suicide gene. / Zhan, Hong; Gilmour, Kimberly; Chan, Lucas; Farzaneh, Farzin; McNicol, Anne Marie; Xu, Jin-Hua; Adams, Stuart; Fehse, Boris; Veys, Paul; Thrasher, Adrian; Gaspar, Hubert; Qasim, Waseem.
In: PLOS ONE, Vol. 8, No. 10, 01.01.2013, p. e77106.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Production and first-in-man use of T cells engineered to express a HSVTK-CD34 sort-suicide gene
AU - Zhan, Hong
AU - Gilmour, Kimberly
AU - Chan, Lucas
AU - Farzaneh, Farzin
AU - McNicol, Anne Marie
AU - Xu, Jin-Hua
AU - Adams, Stuart
AU - Fehse, Boris
AU - Veys, Paul
AU - Thrasher, Adrian
AU - Gaspar, Hubert
AU - Qasim, Waseem
PY - 2013/1/1
Y1 - 2013/1/1
N2 - UNLABELLED: Suicide gene modified donor T cells can improve immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), but can be eliminated in the event of graft versus host disease (GVHD) through the administration of prodrug. Here we report the production and first-in-man use of mismatched donor T cells modified with a gamma-retroviral vector expressing a herpes simplex thymidine kinase (HSVTK):truncated CD34 (tCD34) suicide gene/magnetic selection marker protein. A stable packaging cell line was established to produce clinical grade vector pseudotyped with the Gibbon Ape Leukaemia Virus (GALV). T cells were transduced in a closed bag system following activation with anti-CD3/CD28 beads, and enriched on the basis of CD34 expression. Engineered cells were administered in two escalating doses to three children receiving T-depleted, CD34 stem cell selected, mismatched allogeneic grafts. All patients had pre-existing viral infections and received chemotherapy conditioning without serotherapy. In all three subjects cell therapy was tolerated without acute toxicity or the development of acute GVHD. Circulating gene modified T cells were detectable by flow cytometry and by molecular tracking in all three subjects. There was resolution of virus infections, concordant with detectable antigen-specific T cell responses and gene modified cells persisted for over 12 months. These findings highlight the suitability of tCD34 as a GMP compliant selection marker and demonstrate the feasibility, safety and immunological potential of HSVTK-tCD34 suicide gene modified donor T cells.TRIAL REGISTRATION: ClinicalTrials.gov NCT01204502 <NCT01204502>
AB - UNLABELLED: Suicide gene modified donor T cells can improve immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), but can be eliminated in the event of graft versus host disease (GVHD) through the administration of prodrug. Here we report the production and first-in-man use of mismatched donor T cells modified with a gamma-retroviral vector expressing a herpes simplex thymidine kinase (HSVTK):truncated CD34 (tCD34) suicide gene/magnetic selection marker protein. A stable packaging cell line was established to produce clinical grade vector pseudotyped with the Gibbon Ape Leukaemia Virus (GALV). T cells were transduced in a closed bag system following activation with anti-CD3/CD28 beads, and enriched on the basis of CD34 expression. Engineered cells were administered in two escalating doses to three children receiving T-depleted, CD34 stem cell selected, mismatched allogeneic grafts. All patients had pre-existing viral infections and received chemotherapy conditioning without serotherapy. In all three subjects cell therapy was tolerated without acute toxicity or the development of acute GVHD. Circulating gene modified T cells were detectable by flow cytometry and by molecular tracking in all three subjects. There was resolution of virus infections, concordant with detectable antigen-specific T cell responses and gene modified cells persisted for over 12 months. These findings highlight the suitability of tCD34 as a GMP compliant selection marker and demonstrate the feasibility, safety and immunological potential of HSVTK-tCD34 suicide gene modified donor T cells.TRIAL REGISTRATION: ClinicalTrials.gov NCT01204502 <NCT01204502>
U2 - 10.1371/journal.pone.0077106
DO - 10.1371/journal.pone.0077106
M3 - SCORING: Journal article
C2 - 24204746
VL - 8
SP - e77106
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 10
ER -