NHS Executive South East Region Deanery



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Cancer Research UK Centre

University of Southampton Faculty of Medicine

School of Cancer Sciences

CLINICAL RESEARCH TRAINING FELLOW

Introduction

This appointment will be based within the Cancer Research UK Centre at Southampton General Hospital. The medically-qualified post-holder will join a large team of basic and clinical researchers with extensive programmes in translational cancer medicine. It is designed to provide a period of protected research for a Clinical Fellow who wishes to train for a higher degree in any field relevant the programmes of the Centre: medical oncology, radiation oncology, paediatric oncology, surgery, pathology or other disciplines. It is designed to fulfill the requirements for an out-of-programme experience for a specialist trainee in one of these fields, but may also be suitable for an individual who does not yet have a national training number and wishes to pursue a career in the cancer field.

The Cancer Research UK Centre

The Southampton clinical academic training programme in cancer research has a successful record of training Clinical Research Fellows (15 in the last 7 years) and Clinician Scientists (3 in the last 7 years), embedded in a research-intensive medical school and NHS Trust. Southampton is among the top recruiters in the country to clinical cancer research studies, with around 3500 patients a year enrolled.

The Southampton Cancer Centre incorporates all the elements required to train the best clinical academics. As well as the CRUK Centre, there is the CRUK/NIHR Experimental Cancer Medicine Centre, the newly-built £25M Centre for Cancer Immunology, the CRUK Clinical Trials Unit, the NIHR Clinical Research Facility, the Wessex Investigational Science Hub and a comprehensive cancer treatment centre serving a population of 2-3M, all on a single campus. This incorporates site-specialised medical and clinical oncology, specialist radiotherapy including the first UK service for intraoperative adjuvant brachytherapy for colorectal cancer, paediatric oncology, level 4 haemato-oncology with allogeneic transplantation and cellular therapies, and specialised regional surgical services including neurosurgery, cardiothoracic, oesophagogastric and hepatobiliary surgery.

The training programme is strategically focused on the core themes of the Centre, drawing on our expertise in translational research and cross-disciplinary links to other parts of the university, particularly physical sciences and mathematics.

The research of the Centre in Southampton is principally concerned with new treatment - specifically, immunotherapy - and optimisation through understanding mechanisms of action. Work in cancer prevention is expanding, focused on the interaction between nutrition and cancer risk, particularly breast cancer. There is increasing interest in early detection, including a collaboration with the Southampton-led NIHR school of primary care research CANDID study, with 20 000 patients consulting GPs for respiratory or abdominal symptoms enrolled on a programme of biomarker and clinical outcomes research.

Research themes in the CRUK Centre:

The Southampton Centre has a clear focus on applying discovery science at the translational interface with human cancer, in particular in cancer immunology and the tumour microenvironment. Within this there are a number of broad themes:

Mechanisms in adaptive immunity (Prof T Elliott, Prof E James, Prof A Al Shamkhani)

This work focusses on two major areas. The first is mechanisms of processing and presentation of cellular antigens to cytotoxic T lymphocytes. There are close links to structural biology in the Institute for Life Sciences, and Microsoft Research UK to elucidate the basis of T cell epitope selection. The group published a landmark study combining computational systems modelling, molecular dynamics simulation and cellular immunology to define the mechanism of peptide selection by MHC I in collaboration with Microsoft Research (Bailey, Science Reports 2015). Recent papers have demonstrated the fundamental structural characteristics of different components of the antigen processing apparatus and how these determine the repertoire of peptides presented to the immune system (Reeves, PNAS 2014; van Hateren, J Biol Chem 2017; Elliott Biochemistry 2018; Elliott, Nat Chem Biol 2018). These mechanistic studies synergise with the work of the Southampton-Oxford-La Jolla Centres network Accelerator which is examining the relationship between the tumour mutanome and the presentation of peptide to T cells in tumours. The second area focusses on mechanisms of T cell activation and differentiation. The group has published extensively on mechanisms by which various members of the TNF receptor superfamily affect activation of naïve, memory and exhausted T cells (Buchan J Immunol 2015; Buchan et al Blood 2018; Buchan Clin Can Res 2018; Buchan Immunity 2018). They have also found that the Akt kinase is essential for CD8 effector-like memory T cell development and tumour immune surveillance (Rogel PNAS 2017). These mechanistic studies have identified a number of potential strategies to enhance anti-tumour immunity and/or boost the efficacy of cancer vaccines.

B-cell malignancies (Prof P Johnson, Prof G Packham, Prof A Davies, Prof J Strefford, Prof F Forconi)

This theme encompasses the mechanisms of malignant transformation in B-cells and translational research in the clinic. The convergent theme here is that events downstream of the B-cell receptor are potential targets for novel therapies (Carter, Leukemia 2017; Yeomans, Blood 2016; Linley, Blood 2015) and this has proven accurate, with clinical trials using PI-3 kinase and Bruton tyrosine kinase (BTK) inhibitors showing high response rates in low grade lymphomas (Gopal, NEJM 2014; Wang, NEJM 2014). Our work with the CRUK Centre for Drug Development includes novel antibody trials with anti-CD32 and anti-CD27 reagents, developed from our previous laboratory work and now in phase I/II studies. In addition, we have capitalised on the platform of our collaborative consortium in precision medicine for aggressive B-cell lymphoma (Sha, J Clin Oncol 2018) to support new trials of a second generation BTK inhibitor, acalabrutinib (Wang, Lancet 2018).

Antibody therapeutics (Prof M Cragg, Prof S Beers, Dr S Lim, Prof S Ward,Prof R Ober)

This theme draws strongly on collaborations with structural biology and chemistry to derive structure/function relationships for antibody therapies. For example, we investigated effector mechanisms of antibodies against T-cell co-stimulatory molecules and showed how different isotypes can perform different immunomodulatory functions (Buchan, Immunity 2018), and how the conformation of antibody molecules determined by X-ray crystallography, small angle X-ray scattering (SAXs) and molecular dynamics simulations (Sutton, Biophys J 2018) can determine the level of agonism they exert (Yu, Cancer Cell 2018). In work on other agonistic targets, we showed enhanced antibody tumour targeting by myeloid cell recruitment in the presence of CD27 agonists (Turaj, Cancer Cell 2017), an observation now translated into a phase II clinical trial. We have developed first in class agonistic antibodies capable of blocking the inhibitory Fc gamma receptor and are investigating these in lymphoma (Roghanian, Cancer Cell 2015). The newly established Ward/Ober laboratory brings expertise in both applied work and fundamental intracellular imaging analysis with new antibody-drug conjugates (Chao, Nature Methods 2013).

Translational Immunotherapy (Prof C Ottensmeier, Dr J West)

This theme supports an expanding programme of work on the detailed ex-vivo transcriptional analysis of tumour infiltrating T-cells (Ganesan Nature Immunology 2017; Clarke J Exp MEd 2019) linked to the antigenic landscape in tumours at the level of mutanome and proteome. In order to increase the recovery of very fast off-rate peptides, which are lost from the immunopeptidome using standard purification methods, we have developed a microfluidic device that permits very rapid (millisecond to second) buffer transfers using inertial switch fluidics in collaboration with the Centre for Hybrid Biodevices, which can be applied to small numbers of cells, facilitating analysis of serial ex-vivo tumour biopsies. We have a wide collaborative network for experimental immunotherapeutics , covering a number of other centres in the UK and abroad, including the GAPVAC consortium which has been investigating vaccine approaches for glioblastoma (Hilf, Nature 2018).

Tumour microenvironment (Prof G Thomas, Prof T Underwood, Prof A Mirnezami)

This work is centred on the biology of cancer-associated fibroblasts and their role in promoting the malignant phenotype, focusing on signaling pathways that can be targeted for therapy. We showed that a small molecule inhibitor of NOX4 reverses the tumour promoting phenotype of cancer-associated fibroblasts (Hanley, J Natl Cancer Inst. 2018; Ford Cancer Res 2020) and this is now being translated by testing NOX1/4 inhibitors for combination immunotherapy in head and neck cancer. We also found that cancer-associated fibroblast differentiation is inhibited by DDR targeting, identifying a link with tumour-promoting senescence mechanisms (Herranz, Nature Cell Biol 2015; Georgilis, Cancer Cell 2018). We have compared oesophageal cancer-associated fibroblasts to normal fibroblasts by proteomic profiling and identified differentially expressed proteins in a range of pathways which may lead to novel approaches to therapy (Manousopoulou, Br J Cancer 2018), and also characterised novel functional phenotypes using single cell RNA sequencing, mapping the spatial distribution of the cells in tissues using multiplexed image analysis. We are collaborating to develop a novel bioinformatic approach to deconvolute tumours using methylation data (methylcibersort), giving a more accurate description of tumour composition than gene expression (Chakravarthy, Nat Commun. 2018). The colorectal cancer group works on exosomes as mediators of signals in the microenvironment (Ling, Gut 2016; Bhome, Meth Mol Biol 2017; Bhome, Aging 2017). We have been able to show that exosomes and their miRNA content traffic between cancer cells, stromal fibroblasts and T cells, and affect significant molecular pathways in the destination cell. The oesophageal cancer group is part of the national OCCAMS collaboration, giving important insights into the genomic landscape of oesophageal adenocarcinoma (Secrier, Nature Genet. 2016; Noorani, Genome Res. 2017) and is leading efforts to establish predictors of response to neoadjuvant therapies (Noble, Br J Surg. 2017). In collaboration with the Wellcome Trust Sanger Institute we have been able to establish a bank of oesophageal cancer organoids, and these are being combined with cancer-associated fibroblasts and immune cells for the study of single cell transcriptomes in a complex tumour model.

Breast Cancer (Dr E Copson, Prof R Cutress)

This theme combines work on inherited and modifiable risk factors for breast cancer, to investigate host factors which influence the outcome of primary breast cancer and inform primary and secondary prevention strategies (Cutress, Lancet Oncol 2018). Building on our analysis of the effect of germline BRCA1/2 mutations on prognosis in >3000 young onset breast cancer patients (Copson, Lancet Oncol 2018), we are now investigating the pathological and prognostic implications of lower penetrance breast cancer susceptibility genes and polygenic scores. Collaborations with immunological and bioinformatics teams are investigating the relationships between host genotypes and immunological responses to cancer. Our cohort study has also highlighted the significant adverse effect of obesity on breast cancer prognosis (Copson, Ann Oncol 2015). Collaborations with the Southampton Biomedical Research Centre Nutrition theme focus on body composition patterns and nutritional phenotypes, treatment toxicity and outcomes while a parallel workstream with academic psychiatry is focussing on health behaviour and cancer prevention interventions.

Cancer Research facilities

The academic team is fully integrated with the NHS oncology department, and all the site-specialist clinics run with joint medical/radiation oncology input. More than half the Consultants in Oncology run practices at other hospitals in the Network as well as Southampton, and there are large patient flows between the centre and the various units.

• A strong team of clinical academics in oncology/haematology:

o Prof Andrew Davies: Lymphoma

o Prof Francesco Forconi: Lymphoid malignancy

o Prof Peter Johnson: Lymphoma, antibody therapy

o Prof Christian Ottensmeier: Lung Cancer, head and neck cancer, immunotherapy

o Dr Ellen Copson: Breast Cancer, cancer genetics

o Dr Simon Crabb, Urologic Cancer

o Dr Juliet Gray: Paediatric oncology

o Dr Ioannis Karydis: Melanoma, immunotherapy

o Dr Sean Lim: Lymphoma, immunotherapy

• A rapidly-expanding academic department of surgery:

o Prof Ramsey Cutress: Breast Cancer biology

o Prof Alex Mirnezami: Colorectal cancer biology

o Prof John Primrose: Upper GI cancer trials

o Prof Tim Underwood: Oesophageal Cancer biology

o Miss Emma King: Head and Neck Surgery

• A developing programme in academic cancer pathology:

o Prof Gareth Thomas: Head and Neck Cancer biology

o Prof Tony Williams: Clinical Immunology

o Dr Meg Ashton-Key: Haematopathology

The Centre hosts the Wessex network of the NIHR CRN (Cancer Clinical Lead, Dr Matthew Wheater) for a population of 3 million, which currently recruits over 20% of incident cancer cases into clinical trials. There is close integration of the Network and the CR UK Clinical Research Unit which conducts early phase studies, with research nurses from the two teams cross-covering clinics and unified professional leadership through the CR UK Senior Research Nurse (Jac Samuel).

The Southampton Clinical Trials Unit (Director: Professor Gareth Griffiths), has core funding from CR UK and HTA. Since it was established in 2006 this has expanded its activity to include studies in Upper GI and Colorectal cancer, Lymphoma, Breast and Prostate cancer. The Unit benefits from the long-standing excellence in Clinical IT systems developed in the centre and is piloting remote data capture in the academic UK clinical trials arena.

The Southampton Experimental Cancer Medicine Centre (Lead: Professor Andy Davies), with an expanding portfolio of early phase trials, many testing reagents developed in the Southampton laboratories, and carrying out complex immunologic endpoint assays to GCLP.

Location on the Southampton General Hospital campus, which includes the facilities of the Southampton Oncology Centre (Radiation Oncology, Medical Oncology and Clinical Haematology including level 4 transplantation) as well as the full range of general and tertiary specialist medical facilities, including neurosurgery, hepatobiliary and pancreatic surgery, cardiothoracic surgery, paediatric oncology, cellular pathology and molecular diagnostics.

A dedicated and fully-staffed Wellcome Trust Clinical Research Facility is also located in the hospital immediately adjacent to the Medical Oncology ward, for the conduct of early phase clinical trials work.

The Clinical Training Research Fellowship

Southampton has developed a comprehensive 4 year PhD programme in Cell Biology and Immunology of Cancer, led by Tim Elliott, which has been running since 2006. . This provides a year of broad training followed by a three year PhD, although the first year is optional for Clinical Fellows, depending upon their prior experience.

The Centre team has extensive experience of matching Fellows to projects, both full-time and part-time, clinical and non-clinical. Selection is based upon aptitude demonstrated during their undergraduate careers and clinical training, and motivation judged at interview. Fellows may pursue research in both CR UK-funded and other groups within the Centre, and in some cases outside the Centre, where there is an established collaboration and a suitable co-supervisor. All clinical postgraduate students have one clinical co-supervisor.

During the Fellowship there will be opportunities to maintain some clinical practice, typically 1 session per week at most. There will also be opportunities for involvement in the extensive portfolio of clinical trials conducted in the Centre, and where appropriate taking part in the design, funding and regulatory approval of new studies.

9. CONDITIONS OF EMPLOYMENT

The basic salary of this post will be £34,466 - £49,044 p.a. pa (for those who were ST3 or above on 2 August 2019) or £38,693 - £49,036 pa (for those who were below ST3 on 3 August2016)

full time, depending upon experience. Appointments will be for 3 years in the first instance, with the possibility of extension for a further year if required.

10. PERSONNEL AND FINANCIAL SERVICES

11. HOURS OF DUTY

This is a whole-time appointment. There will be no commitment to out of hours cover in this post.

12. VISITING

Informal enquiries (and visits to the Centre subject to COVID-19 restrictions) are welcomed and can be arranged by contacting Professor Peter Johnson (tel: 023 8120 6186 or johnsonp@soton.ac.uk) 

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