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Title: Donor T cells with inducible caspase safety switch following haploidentical transplants
Author: Elfeky, Reem Ahmed
ISNI:       0000 0004 9359 3350
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available