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The University of Southampton
Medicine
Phone:
(023) 8120 8452
Email:
M.S.Cragg@soton.ac.uk

Professor Mark Cragg BSc, PhD

Professor of Experimental Cancer Research, Director of Cancer Pathway Integrated Postgraduate Programme

Professor Mark Cragg's photo

Mark Cragg graduated from Bath University in 1994 with a first class degree in Biochemistry following two successful placements at Glaxo Wellcome and Northeastern University, Boston. He then moved to Southampton, undertaking a PhD in Immunology and Immunochemistry in the Cancer Sciences Unit (CSU). Following his PhD, he was awarded a career track fellowship within the School of Medicine and subsequently obtained a prestigious fellowship with the Leukaemia Research Fund (now Bloodwise). This fellowship involved a period of study in the world-class laboratory of Andreas Strasser at the Walter and Eliza Hall institute in Melbourne. He returned to the UK in 2007, to establish his own research group within Cancer Sciences as a member of the Antibody and Vaccine Group (AVG) based in the Centre for Cancer Immunology.

As a cancer immunologist, my research uncovers how the immune system interacts with cancer cells and how it can be harnessed in the form of immunotherapy to treat malignancy; particularly by using drugs called monoclonal antibodies. Underpinning this biology are a family of receptors called Fc receptors which serve as a link between the antibodies and the immune cells

His research group is interested in two main areas - antibodies and small molecule inhibitors with the aim of understanding how these therapeutics function to delete tumour cells and how they might be augmented. Throughout the strategy undertaken by the group is highly translational with iterative cycling between in vitro experiments, appropriate in vivo model systems and primary clinical material.

The research group typically comprises 8-10 Postdoctoral fellows, several research assistants, 6-8 PhD students and 1-2 clinical research fellows, with many co-managed with other members of the Antibody and Vaccine Group.

Qualifications

BSc, Biochemistry (1st Class), University of Bath (1994)

PhD, University of Southampton (1998)

Appointments held

Chair of Experimental Cancer Biology (2011-)

Cancer Pathway Director for the Integrated PhD programme (2010-)

Director of the Postdoctoral Association (2011-14)

Chair of Centre for Cancer Immunology Steering committee (2020-)

Research interests

The research group is interested in two main areas - antibodies and small molecule inhibitors with the aim of understanding how these therapeutics function to delete tumour cells and how they might be augmented.

Antibody therapy

How monoclonal antibodies (mAb) achieve their therapeutic function is central to their further development. Although all antibodies are theoretically able to engage with the host effector systems of complement and effector cell activation, only a handful of mAb specificities evoke substantial anti-tumour responses. The group is therefore actively pursuing why this is the case and probing means by which the efficacy of mAb might be augmented. In collaboration with Professor Martin Glennie, the group showed that most CD20 mAb are especially potent at activating the complement pathway (Cragg et al. Blood 2003, 2004). The more rare Type II anti-CD20 mAb do not activate complement efficiently or signal for calcium flux but instead evoke a non-apoptotic cell death pathway (Chan et al. Can Res 2004). The group showed that Type II mAb are far superior to Type I mAb in depleting B cells and that this is independent of the ability to activate complement (Beers et al. Blood 2008, 2010, Tipton et al. Blood 2015).

A key discovery of the group relates to the observation that not all anti-CD20 mAb are stable on the surface of primary cells. This work, (Beers et al. Blood 2010) demonstrated that Type I but not Type II are rapidly internalised from the B cell surface and that this results in consumption of the mAb and reduction in their ability to engage key effector functions, both of which reduce the efficacy of these mAb to deplete target cells. Furthermore, primary clinical samples were shown to undergo the same process of internalisation albeit with substantial heterogeneity. Dr Sean Lim, a previous clinical fellow in the lab subsequently demonstrated that this internalisation is precipitated by the expression of the inhibitory FcgRIIB (Lim et al Blood 2011). The utility of high FcgRIIB expression as a poor prognosis biomarker has so far been established in two different studies (Lim et al. Blood 2011; Lee et al. BJH 2014) and recently in a large antibody trial (Nowicka et al Blood Adv 2021).

A related project in the lab explored the potential of anti-FcgRIIB mAb in augmenting immunotherapy and also in regulating immune responses (Williams et al EJI 2011, Williams et al JI 2013). This project took advantage of our unique panel of anti-FcgRIIB reagents and also our novel huFcgRIIB Tg mouse produced in collaboration with Dr Bhav Sheth and Dr Neil Smyth. In particular, we are exploring the ability of these reagents to directly kill tumour cells, modulate intracellular signalling and enhance other mAb reagents such as anti-CD20 mAb. The human work is mediated through a close collaboration with BioInvent International who developed a panel of truly specific FcgRIIB mAb. Using these, we recently showed that mAb-mediated blockade of FcgRIIB is able to potentiate the killing of normal and malignant B cells with rituximab and other direct targeting therapeutic mAb (Roghanian et al. Cancer Cell 2015). These findings are now being examined in the clinic, through funding for the first in human trial through Bloodwise following review and approval through the CR UK NAC. Led from Southampton by Dr Andrew Davis, the trial will aim to assess the safety and utility of the combination treatment in NHL and CLL. Bioinvent have also recently opened a second study in the US, reporting favourable responses in rituximab refractory patients.

The larger FcgR family encompasses a major area of focus for the laboratory and is the theme of our CR UK programme. This programme seeks to link genetic, molecular and clinical data in order to better understand how current mAb therapeutics function and involves a large multidisciplinary team of basic scientists and clinicians across multiple sites. This work is performed with Professor Stephen Beers, Dr Stephen Thirdborough and Professor Jon Strefford, assessing the cellular and genetic regulation of these receptors, respectively (for recent reviews see Dahal et al, Immunological Reviews 2015 and Hargreaves et al. Immunological Reviews 2015; for primary papers see Dahal et al Can Res 2017; Hussain et al Frontiers in Immunology 2019).

Another major area of interest in the lab is the development of agonistic immunostimulatory mAb. Focused largely on members of the TNFR superfamily, the group aims to understand what drives agonism and how best to engineer these reagents (White et al Cancer Cell 2014; Yu et al Cancer Cell 2018, Yu et al Cancer Cell 2020, Yu et al Comms Biol 2021). To achieve this the group use a combination of human knock-in mice, engineered Fc antibodies, FcgR modified mice and blocking antibodies as well as structural and modelling approaches through strong collaborations with Dr Ivo Tews and Professor Jon Essex (Yu et al Cancer Cell 2018, Sutton et al, Biophys J 2018).

Small Molecule Inhibitors

The group has also developed an interest in small molecule inhibitors. Previously the group assessed inhibitors of oncogenic kinases which are hyperactive (through specific mutations) in cancer cells, promoting tumour survival. Understanding how shut-down of these oncogenic kinases results in apoptosis is critical in developing these reagents further for clinical use. In particular, the group are interested in designing novel strategies using a combination of the kinase inhibitors with monoclonal antibodies and small molecule inhibitors. To date the group has shown that Bim is a key BH3-only protein involved in the apoptosis resulting from oncogenic shutdown of the BCR-Abl fusion protein in CML cells (Kuroda et al. PNAS 2006), the activated EGFR in NSCLC cells (Cragg et al. Plos Med 2007) and the mechanism of death evoked by MEK inhibition in B-Raf mutant cells (Cragg et al. JCI 2008). Furthermore, the group are using BH3-mimetics in an attempt to overcome the inherent resistance to apoptosis observed in many tumour cells (Cragg et al. Nat Rev Can 2009; Shimada et al. Exp Hem 2012, Cummin et al Blood Adv 2021).

More recently, the group has taken an interest in how small molecule signalling inhibitors of the BCR can elicit anti-tumour effects both alone and in combination with mAb therapies. This work, led by Dr Matt Carter, is assessing the critical effector mechanisms in each case. Dr Carter recently showed that for maximal signalling for apoptosis through the BCR, Bim Bik and Noxa are all required (Carter et al. CDD 2015). He also showed that Bim is the key target for PI3K inhibition (Carter et al Leukemia 2017), also when used in combination with anti-CD20 mAb and that BET inhibitors synergize with the BH3-mimetic venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression (Cummin et al Blood Adv 2020).

Additional projects

Additional projects in the lab concern the role of polyploid giant cells in the genotoxic resistance of p53 mutated tumour cells. This project is part of a long-standing collaboration with Dr Katrina Erenpreisa (Riga).

Anyone interested in joining the group (graduate studentships, post-doctoral positions (non-clinical and clinical) and overseas fellows are encouraged to contact Professor Cragg directly (msc@soton.ac.uk)

Links

Researchgate: https://www.researchgate.net/profile/Mark_Cragg

Google Scholar: https://scholar.google.co.uk/citations?user=XsWKuX0AAAAJ&hl=en

Research group

Cancer Sciences

Affiliate research groups

Cancer Sciences Research group, Antibody & Vaccine Group, Centre for Cancer Immunology

PhD supervision

23 completed. 9 current.

Faculty of Medicine

Cancer Pathway Director for the Integrated PhD Programme (2010-)

Steering Committee for the new Centre for Cancer Immunology (2013-2020; Member; 2020 - Chair)

Cancer Sciences Operations Board (2018-)

University of Southampton

Director of the Postdoctoral Society (2011 - 2014)

National and International responsibilities

Article reviewer for high impact journals:

Nature, Cancer Cell, Nature Biotechnology, Nature Communications, PLOS medicine, Blood, Journal of Cell Biology, Oncogene, Cancer Immunology and Immunotherapy, Immunology, Journal of Immunology, Journal of Internal Medicine, Leukaemia Research, Apoptosis, Cell death and differentiation, Neoplasia, Clinical and Experimental Immunology, Expert Opinion On Investigational Drugs, The Open Leukemia Journal; Cell Biology International; Current Cancer Therapy Reviews; Experimental Hematology; FASEB J, International Journal of Cancer.

Member of Editorial Advisory Board for:

Open Hematology Journal; Cancer Cell International (2013 - 15), Open Leukemia Journal (2008-); Antibodies (2010-); International Journal of Hematology Research (2014-); Blood (2018-); Exploration of targeted anti-tumor therapy (2020-)

Grant reviewer for funding bodies:

Wellcome, MRC, LLR, Bloodwise, KKLF, AICR, PCUK, CR UK and Dutch Cancer Council (2007-). Fellowship reviewer for Swedish Foundation for Strategic Research (2009-)

External Advisory boards:

LabEx MAbImprove (2015-)

Latvian Biomedical Research and Study centre (2015-)

Prostate Cancer UK (2015-)

Willberry Research (2018-)

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Articles

Book Chapters

Conferences

Letters/Editorials

Review

Integrated PhD Cancer Pathway: Pathway Director and Lecturer on Cell Biology and Immunology modules (2011 - )

Advanced Immunology (Biol3037 and 6068): (2011 - ) Lecturer

NatSci3006: (2020 - ) Lecturer

BIOL3058: (2017 - ) Dragon

Assessor of MedSci projects

Supervisor of BMedSci student

Personal academic Tutor for UGR Medical students

Professor Mark Cragg
Antibody & Vaccine Group, School of Cancer Sciences, Centre for Cancer Immunology Building MP127,
University Hospital Southampton,
S016 6YD


Room Number : SGH/Centre for Cancer Immunology/MP127

Facsimile: (023) 8070 4061

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