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Editing T cell specificity

Alsubki, RA; (2017) Editing T cell specificity. Doctoral thesis, UCL (University College London). Green open access

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Abstract

Allogeneic hematopoietic stem cell transplantation is considered to be the main means of treatment for hematological malignancies. However, disease relapse and graft versus host disease remain the major cause of death post transplantation. To reduce the risk of graft versus host disease and in order to improve the graft versus leukemia effect, genetically engineered T-cells are used to express tumor specific antigens. This is either through the transfer of a recombinant antigen-specific T cell receptor (TCR) or through the introduction of antibody-like recognition in chimeric antigen receptors (CARs) toward tumor-associated antigens. These methods have made substantial advances. Nevertheless, the complexity in modifying and producing autologous specific T-cell products for each patient is a major barrier to the broader application of this approach. In this context, the ability to generate an “off-the-shelf” mismatched donor-derived therapeutic T cell product was investigated. To overcome HLA barriers and to eliminate the risk of graft versus host disease, tailored transcription activator-like effector nucleases (TALENs) knocking out the expression of endogenous T cell receptor was utilised. Also, the potential of engineered meganucleases and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) to disrupt the genomic sequence of the T cell receptor was evaluated. Large numbers of recent clinical trials have suggested that in vivo persistence and expansion having a potent anti-tumor activity of the genetically engineered T cells is crucial to have a robust clinical response. In order to generate a T cell product possessing these previous features, we have investigated the ability to engineer naïve cord blood T cells toward specific tumor antigens. Due to their naivety, the higher telomeres activity, low graft-versus-hostdisease, amongst several other features, have the potential of making cord blood an optimal source for the production of a universal allogeneic engineered T cell therapy. Moreover, preclinical models have demonstrated that culturing naïve T cells in the presence of interleukin-7 and interleukin-15 might retain the modified cells in their naïve like phenotype. In conclusion, delivery of CD19CAR genes using lentiviral vectors into naïve cord blood T cells could form the basis of generating a universal cell bank of therapeutic T cells against B cell lymphoma. With further optimisation to improve efficiency, this could be combined with TALENs for site-specific disruption of the endogenous T cell receptor to eradicate the risk of graft-versus-host disease

Type: Thesis (Doctoral)
Title: Editing T cell specificity
Event: Institution of Child HEalth
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Cord blood T cells, TALENs, CRISPR/Cas9
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1561576
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