Evaluating the Wilms' Tumour Antigen (WT1) as a target for the immunotherapy of malignancies.
Doctoral thesis, UCL (University College London).
The Wilms’ tumour antigen 1 (WT1) is a transcription factor which is over-expressed in several leukaemias and solid tumours. Currently, there is limited information about the expression and immunogenicity of WT1 in prostate cancer. I used immunohistochemistry to analyse WT1 expression in prostate cancer samples and tetramers to detect WT1-specific T cell responses in the peripheral blood. 36% of cancer samples showed nuclear and cytoplasmic staining for WT1, whereas the staining of all normal prostate tissue was limited to the cytosol (p<0.03). Furthermore, WT1-specific T cells which bound tetramer were detectable in the peripheral blood of 2O/38 (53%) prostate cancer patients, ex vivo. Although these T cells did not expand in 2O/20 patients using peptide stimulation with lL2/IL7, a population of WT1-specific CTL accumulated in 3/8 patients following culture with IL15. T cell receptor (TCR) gene transfer is a strategy to circumvent possible impairment of autologous T cell responses against tumour associated antigens such as WT1. However, exogenous and endogenous TCRs are in competition for CD3 chains, which may reduce the expression of the introduced TCR and impair the antigen specific function of transduced T cells. I developed an approach to improve the expression of exogenous TCR chains by co-transducing TCR genes together with the genes encoding the CD3 complex. Transfer of CD3 and TCR genes into primary T cells resulted in up to a 5 fold increase in TCR expression and up to a 9 fold increase in tetramer binding compared to that seen after transfer of TCR genes alone. Furthermore, T cells expressing high levels of TCR/CD3 demonstrated increased sensitivity. This data indicates that the efficacy of TCR expression, and the effector function of gene modified T cells, is substantially enhanced by the co-transfer of CD3 genes.
|Title:||Evaluating the Wilms' Tumour Antigen (WT1) as a target for the immunotherapy of malignancies|
|Additional information:||Authorisation for digitisation not received|
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