Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia
Author(s)
de Lavallade, Hugues Francois
Type
Thesis
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.
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.
Date Issued
2012-11
Date Awarded
2013-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Foroni, Letizia
Rezvani, Katy
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)