Dr Neil Steven

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Neil Steven is a consultant oncologist with a strong interest in immunotherapy clinical trials, particularly in solid cancers, and in virus-associated malignancies.
Position:

Clinical Senior Lecturer, Institute of Immunology and Immunotherapy, University of Birmingham

Honorary Consultant in Medical Oncology, University Hospitals Birmingham

Deputy Clinical Director, CR-UK Clinical Trials Unit

Email: n.m.steven@bham.ac.uk

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Background and Research focus

Neil is a medical oncologist with a strong focus on developing immunotherapy for solid tumours, and in virus-associated malignancies. His research is focussed on the interaction of malignancy, infection and immunity.  He contributes expertise in the design and execution of clinical trials of immune therapy for malignant disease, with emphasis on biological outcome measures to provide proof of mechanism in humans.  

Following clinical training first in infectious disease then in medical oncology, Neil carried out a PhD in Professor Alan Rickinson’s group at Birmingham, his research focussing on the T cell response to Epstein Barr Virus (EBV) during infectious mononucleosis. EBV is a ubiquitous infectious agent, found in the malignant cells in several human cancers.  Neil works with Dr Graham Taylor who invented the MVA-EL therapeutic cancer vaccine, testing this in a UK dose-finding trial for people with EBV+ cancers, and in a parallel trial in Hong Kong (Clin Cancer Res. 2014;20(19):5009-22; Cancer Res. 2013 Mar 15;73(6):1676-88). The team was awarded the CR-UK Translational Research Prize in 2015. Neil is chief investigator for a further UK trial determining the immunogenicity and immune effects of the selected MVA-EL dose, working with a consortium of seven leading UK hospitals.  This work will be submitted for publication at the start of 2019. 

Merkel cell carcinoma (MCC) is a rare aggressive skin cancer affecting mostly older individuals.  About a fifth of patients with MCC have a history of immune suppression, autoimmunity or immune-related malignancy which associates with poorer outcome. Immune-mediated spontaneous regression of MCC has been reported.  The malignant cells harbour Merkel cell virus or are highly mutated, either way creating targets for powerful immune responses.  Neil is chief investigator for the Rational MCC trial (funded by MRC EME) which comprises (i) a prospective trial comparing radiotherapy and surgery as first definitive treatment which has closed at the end of the feasibility phase and (ii) a unique prospective observational study describing patient and disease characteristics at study entry, the treatment pathway, immune competence measurements in blood and the tumour, and outcomes. Rational MCC has currently 64 patients recruited mostly to the observational component and will close to accrual at end November 2018 with 2 years follow up.  The team are currently setting up digital quantitation of T cell infiltration into the primary tissue and are completing real-time assessment of immune competence in assays undertaken on peripheral blood.  A full understanding of the UK MCC population including determination whether clinical laboratory measurements of immune parameters in tumour and blood associate with outcomes will guide development of trials of immune therapy for primary MCC.

Rational MCC builds on pilot studies using  conventional immunohistochemistry and confocal microscopy on primary MCC samples demonstrating stalling of immune cells outside tumour nests and that the few infiltrating tumour nests were functionally inert (Cancers 2014, 6(2), 1047-1064; doi:10.3390/cancers6021047).  Also, Neil is co-investigator for the completed UKMCC01 clinical trial (funded by CR-UK and Novartis) which tested the clinical outcome of the multi-targeted tyrosine kinase inhibitor, Pazopanib, for advanced MCC.  Working with clinical immunologist Dr Alex Richter, he established the protocol for evaluating immune competence in MCC patients using peripheral blood in the context of this trial, to be submitted by end of 2018. 

As a clinician, Neil has developed the targeted and immune therapy service in Birmingham for people with aggressive skin cancers, notably MCC and melanoma.  He was chief investigator (CI) for a phase I trial testing a dendritic cell vaccine targeting melanoma with antigen expression via what was then a novel non-viral transfection system (Gene Therapy 2011 Jun;18(6):584-93) and is working with collaborators on future cellular therapy trials.  The introduction of novel treatment modalities results in altered patterns of response and adverse events and new therapeutic paradigms and algorithms.  It is clear that clinical practice, trial design and scientific questions will be shaped not just by trials but by well-curated clinical and pathological datasets.  To that end, Neil is working to establish a mechanism with exploits the excellent clinical informatics within University Hospital Birmingham, to create a framework for using high quality real-world data.  The early outputs should be a review of all patients with melanoma brain metastases presented in outline to the NCRI brain metastases workshop in March 2018, to be submitted for publication in 2019 and used as the basis of trial design.  Neil is co-applicant on a national programme investigating adverse events, led from Newcastle, and a local project investigating the immune pathology of sicca syndrome led by Dr Ben Fisher, both in relation to patients treated with immune checkpoint inhibitors for cancer.

 

Expertise

Early phase clinical trials; solid tumours;  immunotherapy; melanoma; Merkel Cell Carcinoma; virus-associated malignancies; immune checkpoint blockade.

 

Other activities

Dr Steven is a member of the National Institute of Clinical Research Skin Cancer Clinical Studies Group and chairs the non-melanoma subgroup. He also undertakes selective consultancy for industry if it seems likely the outcome will benefit patients. Dr Steven has undertaken advisory work for the National Institute for Clinical and Healthcare Excellence. Finally, Neil serves a lead advisor on clinical trials for the CIIC grouping.

 

Publications

 

Epstein Barr virus and the development of EBV-specific vaccination

Taylor GS, Steven NM. Therapeutic vaccination strategies to treat nasopharyngeal carcinoma. Chin Clin Oncol. 2016 Apr;5(2):23. doi: 10.21037/cco.2016.03.20. Review.

Taylor GS, Jia H, Harrington K, Lee LW, Turner J, Ladell K, Price DA, Tanday M, Matthews J, Roberts C, Edwards C, McGuigan L, Hartley A, Wilson S, Hui EP, Chan AT, Rickinson AB and Steven NM. (2014) A Recombinant Modified Vaccinia Ankara Vaccine Encoding Epstein-Barr Virus (EBV) Target Antigens: A Phase I Trial in UK Patients with EBV-Positive CancerClin Cancer Res 20(19):5009-22 

Hui EP, Taylor GS, Jia H, Ma BBY, Chan SL, Ho R, Wong WL, Wilson S, Johnson BF, Edwards C, Stocken DD, Rickinson AB, Steven NM and Chan ATC (2013). Phase 1 trial of recombinant Modified Vaccinia Ankara (MVA) encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients. Cancer Res 73(6):1676-88

Rees L, Tizard EJ, Morgan AJ, Cubitt WD, Finerty S, Oyewole-Eletu TA, Owen K, Royed C, Stevens SJ, Shroff RC, Tanday MK, Wilson AD, Middeldorp JM, Amlot PL and Steven NM (2009). A phase I trial of Epstein-Barr virus gp350 vaccine for children with end stage renal failure awaiting transplantationTransplantation 88(8):1025-9

 

Merkel cell cancer

Knight LM, Stakaityte G, Wood JJ, Abdul-Sada H, Griffiths DA, Howell GJ, Wheat R, Blair GE, Steven NM, Macdonald A, Blackbourn DJ and Whitehouse A (2015) Merkel cell polyomavirus small T antigen mediates microtubule destabilisation to promote cell motility and migrationJ Virol 89(1):35-47

Wheat R, Roberts C, Waterboer T, Steele J, Marsden M, Steven NM and Blackbourn D (2014) Inflammatory cell distribution in primary Merkel cell carcinomaCancers (Basel) 6(2):1047-64

 

Immunotherapy against cancer

Marsden JR, Fox R, Boota NM, Cook M, Wheatley K, Billingham LJ, Steven NM (corresponding author); NCRI Skin Cancer Clinical Studies Group, the U.K. Dermatology Clinical Trials Network and the LIMIT-1 Collaborative Group. Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study. Br J Dermatol. 2017 May;176(5):1148-1154. doi: 10.1111/bjd.15112. Epub 2017 Apr 10

Zhuang X, Ahmed F, Zhang Y, Ferguson HJ, Steele JC, Steven NM, Nagy Z, Heath VL, Toellner KM and Bicknell R (2015) Robo4 vaccines induce antibodies that retard tumor growthAngiogenesis 18(1):83-95

Khan MW, Curbishley SM, Chen HC, Thomas AD, Pircher H, Mavilio D, Steven NM, Eberl M and Moser B (2014) Expanded Human Blood-Derived γδT Cells Display Potent Antigen-Presentation FunctionsFront Immunol 5:344

Simpson AA, Mohammed F, Salim M, Tranter A, Rickinson AB, Stauss HJ, Moss PA, Steven NM and Willcox BE (2011) Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restrictionProc Natl Acad Sci U S A 108(52):21176-81

Steele JC, Rao A, Marsden JR, Armstrong CJ, Berhane S, Billingham LJ, Graham N, Roberts C, Ryan G, Uppal H, Walker C, Young LS and Steven NM (2011) Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanomaGene Ther 18(6):584-93

 

Clinical reports

Harrison SR, Tew A, Steven N, Fisher BA. Steroid refractory dermatomyositis following combination dabrafenib and trametinib therapy. Rheumatology (Oxford). 2018 Mar 30.

Ford M, Sahbudin I, Filer A, Steven N, Fisher BA.  High proportion of drug hypersensitivity reactions to sulfasalazine following its use in anti-PD-1-associated inflammatory arthritis. Rheumatology (Oxford). 2018 Aug 13. 

Wilson R, Menassa DA, Davies AJ, Michael S, Hester J, Kuker W, Collins GP, Cossins J, Beeson D, Steven N, Maddison P, Rinaldi S, Jacob S, Irani SR. Seronegative antibody-mediated neurology after immune checkpoint inhibitors. Ann  Clin Transl Neurol. 2018 Mar 25;5(5):640-645. doi: 10.1002/acn3.54