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Medicine

Professor Freda Stevenson MSc, DPhil, FRCPath, FMedSci

Professor of Immunology

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Professor Freda Stevenson is Professor of Immunology within Medicine at the University of Southampton.

As an immunologist aiming to apply molecular understanding to clinical problems, my research has focused on B lymphocytes. This includes two aspects: first, analysis of the ways by which normal human B cells become malignant and second, in developing strategies to activate anti-tumour immunity.

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.

Qualifications

BSc Biochemistry University of Manchester 1960
MSc Biochemistry University of Manchester 1961
DPhil Biochemistry University of Oxford 1964
FRCPath 1995
FMedSci 2000

Appointments held

1965-67 Lecturer in Biochemistry, University of Sydney.

1967-70 Post-doctoral fellow, University of Oxford.
Lecturer in Biochemistry, Oriel College, Oxford.

1970-73 MRC external scientific staff appointment, Tenovus Research Laboratory, Southampton General Hospital.

1973-81 Tenovus post-doctoral fellow in leukaemia research.
Tenovus Research Laboratory, Southampton General Hospital.

1981-95 Principal Scientific Officer, Regional Immunology Service, Tenovus Research Laboratory, Southampton General Hospital.
Honorary Visiting Fellow, University of Southampton.

1995-97 Top Grade Scientific Officer
Honorary Reader in Immunology
, University of Southampton.

1995- Consultant Immunologist, Wessex Immunology Service, Southampton University Hospitals.

1997- Professor of Immunology, University of Southampton

Research

Responsibilities

Publications

Contact

Research interests

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.

1. Hawkins R.E., Zhu D., Ovecka M., Winter G., Hamblin T.J., Long A. & Stevenson F.K. (1994) Idiotypic vaccination against human B-cell lymphoma. rescue of variable region gene sequence from biopsy material assembly as single chain Fv “personal” vaccines. Blood 83:3279-3288.

2. King CA, Spellerberg MB, Zhu D, Rice J, Sahota SS, Thompsett AR, Hamblin TJ, Radl J & Stevenson FK. (1998) DNA vaccines with single chain Fv fused to Fragment C of Tetanus Toxin induce protective immunity against lymphoma and myeloma. Nature Med. 4(11): 1282-1286.

3. Stevenson FK, Rice J, Ottensmeier CH, Zhu D, Buchan SL, Roddick J, King AJ & Savelyeva N (2004). DNA vaccines to attack cancer. Proc Natl Acad Sci, 101 Suppl 2:14646-52.

4. Rice J, Ottensmeier CH, Stevenson FK (2008). DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 8: 108-120.

5. Savelyeva N, King CA, Vitetta ES, Stevenson FK (2005). Inhibition of a vaccine-induced anti-tumor B cell response by soluble protein antigen in the absence of T cell help. Proc Natl Acad Sci 102 (31): 10987-92.

6. Hamblin T.J., Davis Z., Oscier D.G. & Stevenson F.K. (1999) Unmutated immunoglobulin VH genes are associated with a more aggressive form of chronic lymphocyte leukemia. Blood 94(6):1848-1854. [>1000 citations].

7. Mockridge CI, Potter KN, Wheatley I, Neville LA, Packham G, Stevenson FK (2007). Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood 109:4424-4431.

8. Coelho V, Krysov S, Ghaemmaghami AM, Emara M, Potter KN, Johnson P, Packham G, Martinez Pomares L, Stevenson FK (2010). Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins Proc Natl Acad Sci 107:18587-92

Department(s)

Cancer Sciences

Affiliate Department(s)

Cancer Sciences Research group

Teaching/supervisory/national assessment experience

Full -time university lecturer (1965-67).
Regular supervision of PhD, DM and MPhil students (4-5 in post per year).
Regular external (national and international) and internal examiner of PhD students.
Supervision of medical students and clinical fellows on projects and intercalated degrees.
Lecturer on Graduate School Research Training Programme.
National Assessor for Clinical Scientists in Haematology
Examiner in Immunology for Royal College of Pathologists
Lecturer on MRCP courses for clinical trainees.

National Assessor for applications for registration by the Health Professional Council.

Member MRC Committee of Experts

Visiting Professor Johannes Gutenberg University, Mainz 2006-

International External Assessor

 2002/5:
Member of the Scientific Review Panel of the Helmholtz Programme “Cancer Research” Heidelberg, Germany.
Member of the Scientific Review Panel of the Helmholtz Programme “Infection and Immunity” Braunschweig, Germany.
Member of the Scientific Review Panel of the Swiss National Science Foundation: NCCR “Molecular Oncology-From Basic Research to Therapeutic Approaches”, Lausanne, Switzerland
Member, Special Study Section, NIH Centre for Scientific Review, Bethesda, USA.
Member, NIH Experimental Immunology Study Section, Washington.
Permanent Member of the Review Panel: Italian Ministry for Education, University and Research (MIUR-COFIN).
Member of the Board of Experts of the Italian Ministry of Education of the Committee of Research Evaluation.
Member, Scientific Advisory Board, Multiple Myeloma Research Foundation (MMRF), USA.

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Professor Freda Stevenson
Phone: (023) 8120 6923 Fax: (023) 8120 5152 Email: fs@soton.ac.uk

Room Number: SGH/CSB/MP891

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