Cellular and Vaccination-‐based Immunotherapy of Acute Myeloid Leukaemia

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Abstract

    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.
    Date of Award2014
    Original languageEnglish
    Awarding Institution
    • King's College London
    SupervisorFarzin Farzaneh (Supervisor) & Ghulam Mufti (Supervisor)

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