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Type: Journal article
Title: Phase I trial of inducible caspase 9 T cells in adult stem cell transplant demonstrates massive clonotypic proliferative potential and long-term persistence of transgenic Tcells
Author: Zhang, P.
Raju, J.
Ullah, M.A.
Au, R.
Varelias, A.
Gartlan, K.H.
Olver, S.D.
Samson, L.D.
Sturgeon, E.
Zomerdijk, N.
Avery, J.
Gargett, T.
Brown, M.P.
Coin, L.J.
Ganesamoorthy, D.
Hutchins, C.
Pratt, G.R.
Kennedy, G.A.
James Morton, A.
Curley, C.I.
et al.
Citation: Clinical Cancer Research, 2019; 25(6):1749-1755
Publisher: American Association for Cancer Research
Issue Date: 2019
ISSN: 1078-0432
Statement of
Ping Zhang, Jyothy Raju, Md Ashik Ullah, Raymond Au, Antiopi Varelias, Kate H. Gartlan, Stuart D. Olver, Luke D. Samson, Elise Sturgeon, Nienke Zomerdijk, Judy Avery, Tessa Gargett, Michael P. Brown, Lachlan J. Coin, Devika Ganesamoorthy, Cheryl Hutchins, Gary R. Pratt, Glen A. Kennedy, A. James Morton, Cameron I. Curley, Geoffrey R. Hill, and Siok-Keen Tey
Abstract: Purpose: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. Patients and Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 10⁶/kg donor-derived iCasp9-transduced T cells on day + 25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. Results: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/μL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/μL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. Conclusions: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.
Keywords: T-Lymphocytes
Hematologic Neoplasms
Neoplasm Recurrence, Local
Myeloablative Agonists
Treatment Outcome
Lymphocyte Depletion
Transplantation Conditioning
Hematopoietic Stem Cell Transplantation
Time Factors
Middle Aged
Caspase 9
Young Adult
Transplantation, Haploidentical
Rights: ©2019 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-18-3069
Grant ID:
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