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Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia

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Title: Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia
Authors: de Lavallade, Hugues Francois
Item Type: Thesis or dissertation
Abstract: Combining vaccination against leukaemia-derived antigens and treatment with tyrosine kinase inhibitors (TKI) in chronic phase CML is potentially a promising strategy to eradicate a reservoir of TKI resistant leukaemic cells. Previous studies have documented conflicting effects of TKIs on the immune response. I aimed to determine the in vivo immunomodulatory effects of TKIs on T and B-cell immune responses to antigens in patients with CML on TKIs. I first demonstrated that that the B-cell response to H1N1 influenza vaccine was significantly better in patients with CML compared to patients with other haematological malignancies. I then performed a more comprehensive analysis of T and B cell responses to a viral (seasonal influenza) and bacterial (pneumococcus) vaccine. I did not find a significant quantitative or qualitative difference in T cell responses to influenza vaccine in patients with CML on TKI compared to controls. However, I demonstrated that CML patients on TKIs have impaired IgM responses to pneumococcal vaccine, associated with lower frequencies of IgM memory B cells. Moreover, treatment with imatinib was associated with a significant reduction in IgM memory B cells. In vitro co-incubation of B-cells with plasma from CML patients on TKI or directly with imatinib, dasatinib or nilotinib, induced a dose-dependent inhibition of Bruton's tyrosine kinase, a tyrosine kinase essential for B cell signalling and survival. These data suggest that the loss of memory B-cell subsets and impaired humoral immune responses may be driven by the off-target kinase inhibitory activity of TKIs. I further explored the implications of Philadelphia positive (Ph+) lymphopoiesis on B cell function. I found that nearly 50% of CML patients at diagnosis have evidence of Ph+ B lymphopoiesis. Interestingly, the presence of Ph+ B cells predicted for worse prognosis, suggesting the involvement for a more committed progenitor with biphenotypic self-renewal capacity.
Issue Date: Nov-2012
Date Awarded: Oct-2013
URI: http://hdl.handle.net/10044/1/14263
DOI: https://doi.org/10.25560/14263
Supervisor: Foroni, Letizia
Rezvani, Katy
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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