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Donor T cells with inducible caspase safety switch following haploidentical transplants

Elfeky, Reem Ahmed; (2020) Donor T cells with inducible caspase safety switch following haploidentical transplants. Doctoral thesis (M.D(Res)), UCL (University College London). Green open access

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Abstract

Haplo-identical donors are alternative source of hematopoietic stem cells for patients without a more closely matched donor or who need an urgent allogeneic hematopoietic stem cell transplant (HSCT). Because the donor graft for such haploidentical transplants (haplo-HSCT) has a high frequency of alloreactive T cells recognizing the non-shared HLA haplotype, extensive T-cell depletion remains a fundamental prerequisite if the graft is not to cause fatal acute graft-versus-hostdisease (GvHD). While extensive T-cell removal of the graft effectively prevents GvHD, it increases the risk of graft rejection, relapse, viral and opportunistic infections. Consequently, efforts were made to retain the desired T cells while selectively depleting alloreactive T cells (Aversa et al, 2005 and Mielke et al, 2008). Engineered T cells with safety switches have been developed to increase the feasibility of higher numbers of donor-derived T cells whilst providing a tool to control the increased risk of aGvHD that maybe associated with incomplete abrogation of alloreactivity against the recipient [Amrolia et al, 2006]. This thesis presents data from a phase I/II first- in- man use of TCRαβ/CD19 depleted transplant followed by adoptive transfer of genetically modified donor T cells. These donor T cells were modified through gamma-retroviral vector that carried inducible suicide gene (inducible caspase 9; icas9) which makes cells die on exposure to a drug called AP1903. This thesis also examines the development of an alternative lentiviral vector for icas9 gene transfer, investigates the effect of immune suppressive medications on genetically modified T cells and investigates mechanism of resistance to AP1903.

Type: Thesis (Doctoral)
Qualification: M.D(Res)
Title: Donor T cells with inducible caspase safety switch following haploidentical transplants
Event: UCL (university college London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10100442
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