Professor Gary Middleton MB, BS, MD, FRCP

Department of Immunology and Immunotherapy
Professor of Medical Oncology

Contact details

Telephone: +44 (0) 121 414 7144 (PA)
Fax: + 44 (0) 121 414 4486
Email: g.middleton@bham.ac.uk

Address: Department of Immunology and Immunotherapy
University of Birmingham
Edgbaston
Birmingham
B15 2TT

Day in the life of a Professor of Medical Oncology

Gary Middleton is Professor of Medical Oncology in the Department of Immunology and Immunotherapy, Honorary Consultant Oncologist at University Hospitals Birmingham and Director of the Birmingham Experimental Cancer Medicine Centre (ECMC). He drives the translation of Birmingham cancer immunology and genomics science into novel clinical research, collaboratively delivered across the ECMC network. Committed to developing a vibrant next generation of academic oncologists, Gary directs the Birmingham CRUK Clinical Academic Training Programme.

A leader in Precision Medicine oncology, Gary is CI of the National Lung Matrix Trial (NLMT), a paradigm complex innovative platform trial, delivered at all ECMCs. The study outcomes were published in Nature in 2020 (DOI:10.1038/s41586-020-2481-8) and the 2021 DHSC document ‘Saving and Improving Lives: The Future of UK Clinical Research Delivery’ described NLMT as a trial that “shows the power of collaboration, through the UK’s integrated Health Research System”.

Gary is investigating how the genomic, transcriptomic and immunological context of cancers impacts on response to targeted therapy (DOI:10.1016/j.annonc.2021.11.004). As Translational Lead for the DETERMINE study, opening across adult and paediatric ECMCs, he drives the next iteration of UK-led Precision Medicine studies. Keto Lung, his novel Metabolic Precision Medicine programme, will explore the addition of a ketogenic diet to standard chemo-immunotherapy in squamous cell lung cancer, stratifying patients for a targeted metabolic intervention by histology.

Gary’s immunology research focuses on the dynamics and importance of MHC class II expression in colorectal cancer and defining predictive biomarkers for toxicity from checkpoint blockade therapy, seeking to translate findings into novel immunotherapy studies. His group have very recently published the first cellular predictive biomarker from severe immune-related adverse events in lung cancer, identifying a pre-treatment loss of B regs as predictive of severe toxicity (DOI:10.1038/s41467-022-30863-x).

Biography

Gary has extensive experience of developing novel clinical trials, particularly in lung and colorectal cancer, translating Birmingham-led discovery science into patient outcomes. Recent Immunotherapy studies for which he is Chief Investigator (CI) include ANICCA-Class II and PePS2, both Birmingham-led and delivered by the University’s CRCTU. PePS2’s outcomes were published in Lancet Respiratory Medicine (DOI: 10.1016/S2213-2600(20)30033-3) and could open up a new therapy to Performance Status 2 Non-Small-Cell Lung Cancer patients.

Gary’s translational research focuses at present on the dynamics and importance of MHC class II expression in colorectal cancer and defining predictive biomarkers for toxicity from checkpoint blockade. Working in collaboration with Birmingham colleagues Dr Francis Mussai and Dr Carmela de Santo on research into Myeloid Derived Suppressor Cells (MDSCs), he has recently published data on the crosstalk between cancer cells, monocytes and T cells in CRC, describing how CRC polarises monocytes to become M-MDSCs (Cancer Immunology Immunotherapy; DOI: 10.1007/s00262-021-03081-5). Following on from other data from this group identifying CD33 as a novel target for ADC-mediated M-MDSC killing, they have have initiated the phase 0 trial GOTHAM using gemtuzumab ozogamicin with reduction in M-MDSC level as a primary end-point.

Gary is Co-Lead of the UK Coronavirus Cancer Monitoring Project which has investigated outcomes for cancer patients who have tested positive for COVID-19, from over 60 UK centres. UKCCMP has published on the impact of chemotherapy and immunotherapy on these patients, in The Lancet and Lancet Oncology (DOI:10.1016/ S0140-6736(20)31173-9; DOI: 10.1016/S1470-2045(20)30442-3)

Between 2017 and 2022 Gary was Clinical Director of the Cancer Research UK Birmingham Centre, driving the translation of discovery science from the University’s College of Medicine and Health, with a focus on Cancer Immunology, Caner Genomics and Tumour Micro-environment.

Teaching

MSc Clinical Oncology – Molecular Pathology of Cancer
MSc in Blood Sciences
MSc Genomic Medicine – Module Lead
BMedSc

Postgraduate supervision

Gary is currently supervising six PhD students and is particularly interested in training students on tumour immunobiology and defining novel targets for the treatment of lung cancer.

Research

Research interests

Class II expressing microsatellite stable colorectal cancer
Class II dynamics in colorectal cancer
Immunobiology of the tumour microenvironment
Myeloid-derived suppressor cells
COVID mortality risk to cancer patients
BRAF mutant colorectal cancer
Cancer Genomics

Therapeutic areas of interest

Precision Medicine and the genomics of lung cancer
Advanced cellular therapies
Stratified Immunotherapy
Checkpoint blockade therapy

Other activities

National Roles

Chair of the NCRI Lung Group, developing its strategic research portfolio
Member of the NCRI advanced lung sub-group and colorectal sub-group
Member of Cancer Research UK Experimental Medicine Expert Review Panel and member of CRUK Clinical Research Committee.
Translational Lead for the DETERMINE(aDvancing gEnomically maTchEd tReatMents IN rare cancErs) platform trial

Birmingham-led Experimental Research Delivery

Adult and TYA Lead for Birmingham Paediatric ECMC
Birmingham CRCTU Director of Early Phase Trials
Scientific Advisory Board member for Precision Panc

Publications

Recent publications

Stephen Booth, Helen M. Curley, Csilla Varnai, Roland Arnold, Lennard Y. W. Lee, Naomi A. Campton … UKCCMP team (2022, Feb; 196(4):892-901. DOI: 10.1111/bjh.17937). Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy. British Journal of Haematology

Middleton, G., Robbins, H., Andre, F., Swanton, C. (2022, Feb: DOI:10.1016/j.annonc.2021.11.004) A state-of-the-art review of stratified medicine in cancer: towards a future precision medicine strategy in cancer. Annals of Oncology

Patel, A. J., Tan, T. M., Richter, A. G., Naidu, B., Blackburn, J. M., Middleton, G. W. (2022, Feb; DOI: 10.1038/s41416-021-01572-x) A highly predictive autoantibody-based biomarker panel for prognosis in early-stage NSCLC with potential therapeutic implications. British Journal of Cancer

Patel, A. J., Willsmore, Z. N., Khan, N., Richter, A., Naidu, B., Drayson, M. T., ... Middleton, G. W. (2022, June; DOI:10.1038/s41467-022-30863-x) Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade. Nature Communications

Gneo L, Rizkalla N, Hejmadi R, Mussai F, de Santo C, Middleton G. (2021, Nov; DOI: 10.1007/s00262-021-03081-5) TGF-beta orchestrates the phenotype and function of monocytic myeloid-derived suppressor cells in colorectal cancer. Cancer Immunology Immunotherapy

Gary Middleton, Helen Robbins, Fabrice André, Charlie Swanton (2021, Nov 19; DOI: /10.1016/j.annonc.2021.11.004). A state-of the-art review of stratified medicine in cancer: towards a future precision medicine strategy in cancer. Annals of Oncology

Lennard Y.W. Lee, Thomas Hill, Oliver Topping, Michael Tilby, Mark Baker, Julian Greig … Gary Middleton, on behalf of the UK Birmingham Chemotherapy Cancer COVID-19 Project (2020, Sept 14; DOI: 10.1016/j.ccell.2020.07.009). Utility of COVID-19 screening in cancer patients. Cancer Cell

Lennard Y W Lee, Jean-Baptiste Cazier, Thomas Starkey, Sarah E W Briggs, Roland Arnold … Gary Middleton, Rachel Kerr, on behalf of the UK Coronavirus Cancer Monitoring Project Team (2020 Oct 1; DOI: 10.1016/S1470-2045(20)30442-3). COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics. Lancet Oncology

Gary Middleton, Kristian Brock, Joshua Savage, Rhys Mant, Yvonne Summers, John Connibear … Lucinda Billingham (2020, Sept; DOI: 10.1016/S2213-2600(20)30033-3). Pembrolizumab in patients with non-small cell lung cancer and a performance status of 2 (PePS2): a single-arm phase II trial. Lancet Respiratory Medicine.

Oliver J Pickles, Aneta Drozd, Louise Tee, Andrew D Beggs, Gary W Middleton (2020, Aug; DOI: 10.18632/oncotarget.27681) Paradox breaker BRAF inhibitors have comparable potency and MAPK pathway reactivation to encorafenib in BRAF mutant colorectal cancer. Oncotarget

Gary Middleton, Peter Fletcher, Sanjay Popat , Joshua Savage , Yvonne Summers … Charles Swanton, Lucinda Billingham (2020, July 15; DOI: 10.1038/s41586-020-2481-8). The National Lung Matrix Trial of personalized therapies in lung cancer. Nature.

Lennard YW Lee, Jean-Baptiste Cazier, Vasileios Angelis, Roland Arnold, Vartika Bisht, Naomi A Campton … Gary Middleton, on behalf of the UK Coronavirus Cancer Monitoring Project Team (2020, June 16; DOI: 10.1016/S0140-6736(20)31173-9). COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments. The Lancet

Oliver J. Pickles, Lennard Y. W. Lee, Thomas Starkey, Luke Freeman-Mills, Anna Olsson-Brown, Vinton Cheng … Gary Middleton (2020, June 16; DOI: 10.1038/s41416-020-0930-7). Immune checkpoint blockade: releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome? British Journal of Cancer

Valerie Pestinger, Matthew Smith, Toju Sillo, John M. Findlay, Jean-Francois Laes, Gerald Martin, Gary Middleton, Phillipe Taniere, Andrew D. Beggs (2020, June 1; DOI: 10.1007/s40291-020-00462-x) Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants. Molecular Diagnosis and Therapy

Gary Middleton, Yiqun Yang, Catarina D. Campbell, Thierry André, Chloe E. Atreya, Jan H.M. Schellens … Ryan B. Corcoran (2020, Feb 11; DOI: 10.1158/1078-0432.CCR-19-3579). BRAF-mutant transcriptional subtypes predict outcome of combined BRAF, MEK, and EGFR blockade with dabrafenib, trametinib, and panitumumab in patients with colorectal cancer. Clinical Cancer Research

Akshay J. Patel, Alex Richter, Mark T. Drayson, Gary W. Middleton (2020, Jan 4; DOI: 10.1007/s00262-019-02461-2). The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer. Cancer Immunology, Immunotherapy

Livingstone F., Panetti S., Margaret N., Collins P., Graef S., Nagy S., Booth S., Lenton R., Noyvert B, Shannon-Lowe C., Middleton G., Mussai F., De Santo C. (2019, Sept; DOI: 10.1016/j.ebiom.2019.08.025) MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers. Ebiomedicine

Swati Khanna, Suzanne Graef, Francis Mussai,  … Gary Middleton (senior author), Carmela De Santo, Raffit Hasan (2018, March 30: DOI: 10.1158/1078-0432.CCR-17-3757) Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients. Clinical Cancer Research

Neeraj Lal, Brian S White, Ghaleb Goussous, Oliver Pickles, Mike J Mason, Andrew D Beggs … Gary W Middleton (2017, Oct 23; DOI: 10.1158/1078-0432.CCR-17-1090). KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer Clinical Cancer Research

Neeraj Lal, Andrew Beggs, Benjamin Willcox, Gary Middleton (2015 Apr 2; DOI: 10.4161/2162402X.2014.976052) An immunogenomic stratification of colorectal cancer: implications for development of targeted immunotherapy. Oncoimmunology.

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