About
My research has focussed on myeloid haematological malignancy since 1983. I co- initiated the Cardiff research programme into myelodysplastic syndromes, where my in vitro and clinical observations generated several first-author papers, including in the NEJM and Lancet.
In Liverpool from 1991, my focus shifted to chronic myeloid leukaemia (CML), initially studying antisense therapeutics targetting BCR-ABL1, including clinical studies of marrow purging at transplantation. This evolved to studies on the immunogenicity of BCR-ABL. My group showed for the first time that cytotoxic T lymphocytes (CTL) recognising BCR-ABL peptides can be induced from normal and CML blood, which will kill CML cells in vitro. Using mass spectrometry, I then showed that BCR-ABL peptides are expressed on HLA molecules on the CML cell surface. This was the first direct demonstration of any tumour-specific immunological target, and led to my clinical trial of CML patient vaccination with BCR-ABL peptides. This elicited BCR-ABL directed CTL and molecular regression of the disease.
My CML group has been extensively involved in the large clinical trials of tyrosine kinase inhibitors (TKI), which have transformed outlook from a median survival of ~5 years to normal life expectancy for ~90% of patients. We discovered that cellular imatinib uptake is mediated by human Organic Cation Transporter 1 (hOCT1); this highly cited work was the first demonstration of cancer treatment requiring active uptake for efficacy. A more recent contribution is that high cancerous inhibitor of PP2A (CIP2A) levels confer a high probability of transformation if treated with imatinib. Since then, >150 studies have shown analogous findings in all of 21 different tumours. In CML, the adverse effect of high CIP2A is overcome by newer TKI, and we have recently submitted for publication our work demonstrating similar findings in AML. CIP2A research remains a central theme, focussing on its structure and binding partners and why some but not all malignancies have high CIP2A
My group has been central to many clinical trials (some with me as Chief Investigator) in both CML and AML. These include my major part in a practice changing international study demonstrating that nilotinib may be superior to imatinib and 2 recent senior-author papers from large phase III studies of the UK AML group investigating dose alteration of daunorubicin and of clofarabine. I am also Chief Investigator for DESTINY, a UK-wide ongoing study of gradual withdrawal of CML treatment, which currently has the best results in the world for treatment cessation in suitable CML patients. Finally, I have recently co-chaired a European LeukaemiaNet (ELN) working party on adverse effects of current CML treatment and have been a member of the ELN CML treatment guidelines group since 2010.
I chaired the National Cancer Research Institute (NCRI; formerly MRC) subgroup on CML from 2007-13, and chaired the European Haematology Association Scientific Working Group on CML for 2014.