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Breaking T-cell tolerance in chronic lymphocytic leukaemia

Wong, Ryan 2013. Breaking T-cell tolerance in chronic lymphocytic leukaemia. PhD Thesis, Cardiff University.
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CLL is an incurable B-cell malignancy associated with profound tumour cell-mediated immune dysfunction. It therefore represents a challenging disease for the successful application of immunotherapeutic strategies aimed at promoting anti-tumour T-cell responses. In this study, extensive immunophenotypic analysis of T-cells from the blood of CLL patients was performed, in order to better characterise their dysfunctional status within the disease. Analysis of CLL patient blood samples revealed a skewing of T-cells towards a highly differentiated effector memory phenotype as well as the expression of markers associated with exhaustion/senescence (CD28- and CD57+) and immunosuppressive molecules (PD-1 and CD200). In addition this study revealed the expansion of CD8+ T-cells in a subset of CLL patients leading to an inversion in the normal CD4:CD8 ratio. The presence of an inverted CD4:CD8 ratio was subsequently shown to be associated with a shorter time to first treatment and reduced progression-free survival. Characterisation of T-cells identified several molecules that could be targeted therapeutically in order to break T-cell tolerance in CLL patients and potentially restore normal immune responses. Investigation of the immunosuppressive molecules PD-1 and CD200 showed that they are over expressed in CLL patients, suggesting that they may be involved in maintaining T-cell tolerance in the disease. However, blockade of PD-1-PDL-1 and CD200-CD200R signalling pathways failed to enhance T-cell responses from CLL patients in vitro. Investigation of an alternative approach to enhance T-cell responses in CLL involved the use of a bi-specific antibody targeting CD19 and CD3 called blinatumomab. In vitro testing showed that blinatumomab can induce T-cell activation, promoting the release of pro-inflammatory cytokines and granzyme B secretion from both CD4+ and CD8+ T-cells. In addition, blinatumomab was shown to mediate T-cell dependent killing of CLL cells requiring the formation of T-cell:CLL cell conjugates. Finally this study provided clear evidence that blinatumomab can break T-cell tolerance in CLL and strongly advocates the progression of blinatumomab into clinical trials as a novel therapeutic agent in CLL.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Funders: Cancer Research Wales
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:17

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