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Title: Development of a vaccine for the immunotherapy of acute myeloid leukaemia by the modification of autologous leukaemia cells
Author: Roddie, Patrick Huw
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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The hypothesis represented within this study is that modification of leukaemia cells in order to allow expression of costimulatory molecules and/or production of immunostimulatory cytokines would render these cells capable of generating autologous leukaemia reactive CTLs. Two main approaches were employed in an attempt to test this hypothesis. The first was based on the transfer of genes encoding costimulatory molecules and immunostimulatory cytokines to leukaemia cells. The second approach involved the attempted differentiation of leukaemia cells to dendritic-like cells (DLLC) by the use of specific cytokine combinations. Leukaemia cells from 42 patients with AML were tested for evidence of differentiation following their culture with cytokines GM-CSF, IL-4 and TNFa/CD40 ligand. In 22 cases the leukaemia cells were deemed to have undergone DLLC differentiation based on upregulation of expression of costimulatory molecules and dendritic cell associated markers, as measured by flow cytometry, and the acquisition of a dendritic-cell like morphology. Antigen presenting function was measured in mixed leukaemia lymphocyte reactions where DLLC were found to be potent stimulators of allogeneic T lymphocyte proliferation. In 2 cases co-culture of DLLC with autologous T lymphocytes led to the generation CTLs that were capable of recognising and destroying unmodified cells in cytotoxicity assays. In 4 cases the leukaemia cells had poor viability of the culture period and were therefore not evaluable. In the remaining 16 cases the leukaemia cells were deemed to be resistant to cytokine induced differentiation. Examination of the clinical features of these cases showed a preponderance of poor risk karyotypic features. A variety of differentiating agents were used in combination with cytokines in an attempt to overcome differentiation resistance. Bryostatin-1 was found to be successful in permitting DLLC differentiation to proceed but only in a proportion of the resistant cases. In summary DLLC derived from leukaemia cells by cytokine induced differentiation might be suitable for use as vaccines for the immunotherapy of AML.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available