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Title: Cellular and vaccination-based immunotherapy of acute myeloid leukaemia
Author: Krishnamurthy, Pramila
ISNI:       0000 0004 5368 1815
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Approximately 50% of Acute Myeloid Leukaemia (AML) patients relapse within 5 years of diagnosis. Allogeneic haematopoietic stem cell transplantation (HSCT) has curative potential, partly mediated by a Graft-versus-Leukaemia (GvL) effect. GvL activity may be boosted by donor lymphocyte infusions (DLI) after HSCT, given pre-emptively (pDLI), to prevent relapse in mixed donor chimeric recipients, or therapeutically (tDLI) following disease recurrence. Few publications report efficacy of these approaches, therefore a retrospective analysis of outcomes after DLI at our institution, following lymphodepleted, reduced intensity conditioned HSCT for AML/myelodysplastic syndromes (MDS), was performed. Encouraging estimated 5-year overall survival rates following DLI of 80% for pDLI recipients and 40% for tDLI recipients were observed. Incidence of GvHD was only moderate, suggesting delayed add-back of immune cells can boost GvL reactions in AML/MDS patients without excessive toxicity. However, despite association of DLI with reduced relapse, leukaemia recurrence in a proportion of patients highlights that GvL activity is neither guaranteed nor universally sustained. Two forms of vaccination are described in this thesis, aiming to enhance priming and activity of leukaemia-reactive T-cells. Both offer broad applicability across all human leucocyte antigen (HLA)-types. T-cell responses to peptide vaccinations targeting the leukaemia-associated antigen Wilms’ Tumour protein (WT1) were enhanced by exploration of novel adjuvants for induction of cell-mediated immunity. Vaccinations comprising these adjuvants and single peptides or overlapping peptides spanning the whole WT1 protein, induced functional T-cell responses (antigen-specific in vivo cytolytic activity and interferon-gamma production) in C57BL/6 mice. Secondly, autologous AML blasts, genetically modified to express the immunostimulatory molecules CD80 and IL-2, were co-administered as a vaccine with tDLI in a Phase I clinical trial. Preliminary data supporting safety of this approach and possible induction of immune responses to vaccination, evidenced by development of a delayed-type hypersensitivity reaction in a subject, are presented. This thesis describes broad-based immunotherapeutic strategies in AML patients for prevention of disease recurrence by enhancement of anti-leukaemic immune responses.
Supervisor: Farzaneh, Farzin ; Mufti, Ghulam Jeelani Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available