Manipulation of the tumour microenvironment in chronic lymphocytic leukaemia : investigation of a novel therapeutic strategy

• Main Author: Cuthill, Kirsty May
• Other Authors: Devereux, Stephen ; Pepper, Andrea Gail Sherman
• Published: King's College London (University of London) 2017
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733335

The aim of this thesis was to investigate whether manipulation of the tumour microenvironment can suppress the proliferation of malignant cells in Chronic Lymphocytic Leukaemia (CLL). It has been established the CLL cells undergo proliferation in the lymph-node compartment, where they interact with components of the tumour microenvironment including activated CD4 T cells. We therefore explored whether T cell suppression using ciclosporin (CsA) could inhibit the activation and proliferation of CLL cells. A series of in-vitro assays was developed to characterise the effect of CsA on CD4 T cells in CLL. In view of the fact that CsA inhibits NFAT (Nuclear Factor of Activated T cells), which plays a role in B cell receptor (BCR) signalling in CLL, we investigated whether CsA has a direct effect on malignant cells. Having shown that CsA has a major T cell-dependent effect and a smaller direct effect on the activation of CLL cells in-vitro, we developed a Phase 2 clinical trial (CyCLLe) to investigate the effect of CsA on the proliferation of CLL cells in patients with early stage, adverse risk disease. The proliferation of CLL cells was measured using in-vivo deuterium labelling, a novel method of assessing drug effect. Despite the promising in-vitro findings, CsA did not inhibit in-vivo proliferation. A further study of in-vivo labelling was designed to assess intra-patient variation in proliferation rates in CLL. Using ‘pulse-labelling’ with deuterated glucose, it was possible to investigate the trafficking of CLL cells between the lymph-node and peripheral blood. Furthermore, it was possible to explore the relationship between sIgM expression, proliferation and trafficking of CLL cells. Importantly, these studies found that in patients with mutated IgVH genes, there is an apparently independent sub-population of cells, characterised by low sIgM expression and low BCR internalisation that is quiescent.