Abstract
Approximately 50% of Acute Myeloid Leukaemia (AML) patients relapse within5 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 Award | 2014 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Farzin Farzaneh (Supervisor) & Ghulam Mufti (Supervisor) |