Stevenson, Freda - University of Southampton

个人简介

Professor Stevenson has been involved in the initiation and establishment of research into lymphoma for which the University of Southampton is now widely recognized. She pioneered the use of immunogenetics to probe the origin and behaviour of B-cell malignancies and she is the author of >250 papers. A particularly important paper, identified in the Focus on Haematology section of Blood, described how the immunoglobulin gene status in cases of chronic lymphocytic leukaemia (CLL) acts as a major prognostic factor. The paper has been cited >1500 times and the findings are having a significant impact on the management of this disease. It has led to drug targeting of immunoglobulin signalling pathways which are inducing remissions in a wide range of patients. In 2015, she was awarded the Rai-Binet medal for her work on chronic lymphocytic leukemia by the International Workshop on CLL. The second area of research began from investigating the use of surface idiotypic Ig on B-cell tumours as a target for immune attack. Using the idiotypic antigen, she developed genetic vaccines in which DNA encoding a tumour antigen linked to an alert signal is injected directly (Nature Medicine 1998). Application of these novel vaccine designs to other antigens expressed by various cancers followed, with clinical application via a collaboration with Prof Christian Ottensmeier/Dr Natalia Savelyeva. In 2014 Professor Stevenson received the Jean Bernard Lifetime Achievement award from the European Haematology Association for this work. Professor Stevenson is an elected Fellow of the Academy of Medical Sciences and is an Associate Editor of the top haematological journal Blood.

研究领域

Her research interests continue in the field of human B-cell malignancies working closely with Dr Francesco Forconi on the effects of new drugs in CLL. She also works with Prof Graham Packham on the pathogenesis of human follicular lymphoma with novel findings reported (Proc Natl Acad Sci 2010), and on signalling pathways operating in normal and malignant human B cells, with new significant findings already published. DNA fusion vaccines against cancer Gene-based vaccines harness genetic technology to immunological understanding and are the likely future for curing cancer brought into remission by conventional treatments. Using the safe idiotypic (Id) antigen from lymphoma as a model for testing vaccine design and construction, the Ig genes from patients’ material can be assembled as single chain Fv to activate immunity.1 Finding the immunogenicity of Id antigen to be low, we initiated the approach of fusing pathogen-derived genes to the tumor antigen to amplify the immune response.2 This proved to be a turning point, revealing the concept that fusion genes containing non-toxic sequences from infectious organisms can activate linked T-cell help, critical for both antibody and T-cell responses against the attached tumor sequence.3 Recent studies have shown that activating the non-tolerized anti-pathogen CD4+ T cell repertoire is important in overcoming tolerance. Initial designs are in clinical trial for patients with lymphoma and are showing immune responses against Id antigen. Other surface antigens can also be targeted.4 The next important observation was that, unless T-cell help is maintained, vaccine-induced B-cell responses can by suppressed by leaking tumor antigen.5 We then designed minimized fusion genes to induce specific cytolytic T-cell responses against intracellular tumor antigens.4 Minimizing was an important modification to avoid introducing competitive MHC Class I-binding sequences. An additional novel approach was to place a tumor epitope sequence at the C-terminus of the fusion gene which assists processing and presentation, opening the design for a wide range of defined tumour antigens.4 An epitope from prostate-specific membrane antigen is now in trial for patients with prostate cancer, using electroporation. This technique appears to overcome the apparent block in translating DNA vaccination to human subjects. Assessment of immune responses in the first 20 patients show robust vaccine-induced CD8+ T-cell responses against the target tumor cell antigen in 70%. This is a striking validation of a strategy developed in pre-clinical models operating successfully in the clinic. The next trial will target an antigen on chronic myeloid leukaemia, clinically maintained but not cured by tyrosine kinase inhibitors (Imatinib), where again pre-clinical validation has been made. Immunogenetics to define B-cell malignancies We first showed that chronic lymphocytic leukaemia is not a single disease as previously thought, but consists of two subsets, distinguished by the mutational status of the Ig variable region genes.6 Importantly, the unmutated subset has a much worse prognosis than the mutated, and the latter may not require treatment. This finding is informing the management of CLL. We have correlated the two subsets with differences in signalling via the surface IgM, and made the surprising observation that anergic pressure via signaling in vivo can be reversed in vitro.7 For follicular lymphoma, we made the first observation that most, possibly all, cases have N-glycosylation sites in their variable regions introduced by somatic mutation. These positively selected sites acquire unusual oligosaccharides, able to interact with stromal lectins.8 This could bypass the need for antigen to maintain tumour survival in the germinal center, and therapeutic strategies could be aimed at blockade. Our studies of immunogenetics have illuminated pathogenesis and prognosis, and are revealing potential treatments for a range of B-cell tumours.

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IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus - Drennan, S., D'Avola, A., Gao, Y., Weigel, C., Chrysostomou, E., Steele, A.J., Zenz, T., Plass, C., Johnson, P.W., Williams, A.O., Packham, G., Stevenson, F.K., Oakes, C.C. and Forconi, F. Published:2017Publication:LeukemiaPage Range:1-9doi:10.1038/leu.2016.356PMID:27890932 PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells - Yeomans, Alison, Lemm, Elizabeth, Wilmore, Sarah, Cavell, Breeze, Valle-Argos, Beatriz, Krysov, Sergey, Hidalgo, Marina, Leonard, Elodie, Willis, Anne E., Forconi, Francesco, Stevenson, Freda, Steele, Andrew, Coldwell, Mark and Packham, Graham Published:2016Publication:OncotargetPage Range:1-13doi:10.18632/oncotarget.11655PMID:27579538 Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL - D'Avola, Annalisa, Drennan, Samantha, Tracy, Ian, Henderson, Isla, Chiecchio, Laura, Larrayoz, Marta, Rose-Zerilli, Matthew, Strefford, Jonathan, Plass, Christoph, Johnson, Peter W., Steele, Andrew J., Packham, Graham, Stevenson, Freda K., Oakes, Christopher C. and Forconi, Francesco Published:2016Publication:BloodPage Range:1-25doi:10.1182/blood-2016-03-707786PMID:27301861 Targeting carcinoembryonic antigen with DNA vaccination: on-target adverse events link with immunological and clinical outcomes - Mccann, Katy J., Mander, Ann, Cazaly, Angelica, Chudley, Lindsey, Stasakova, Jana, Thirdborough, Stephen M., King, Andrew, Lloyd-Evans, Paul, Buxton, Emily, Edwards, Ceri, Halford, Sarah, Bateman, Andrew, O'Callaghan, Ann, Clive, Sally, Anthoney, Alan, Jodrell, Duncan I., Weinschenk, Toni, Simon, Petra, Sahin, Ugur, Thomas, Gareth J., Stevenson, Freda K. and Ottensmeier, Christian H. Published:2016Publication:Clinical Cancer ResearchPage Range:1-33doi:10.1158/1078-0432.CCR-15-2507 PMID:27091407