Research Area
Our work has traditionally focussed on T-cell ligands and the receptors that recognise them. More recently, we have become interested in precisely what T-cells target during successful immunotherapy for solid cancer or during natural spontaneous remission. This has necessitated that we build pipelines for the discovery of what T-cell receptors (TCRs) of unknown specificity recognise. These pipelines have enabled us to determine that many of the T-cells from these remarkable patients have capacity to recognise most forms of cancer via new mechanisms. We aim to use these TCRs and the ligands they recognise to build the next generation of cancer therapies.
Team Description
Our diverse, passionate and dedicated group believe that we can learn from those rare individuals that clear end-stage solid cancers and build the next generation of successful immunotherapies for cancer
Team Members
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Publications
TEN SELECTED RELEVANT PUBLICATIONS
1. Liddy et al (2012) Monoclonal TCR-redirected tumour cell killing Nature Medicine, 18, 980-7. Nat Liddy (first author) was a Sewell group PhD students at time of publication. Featured in article “Monoclonal T-cell receptor drugs pique pharma’s interest” Nature Biotechnology, 30, 950-951. This technology resulted in the first ever T-cell receptor based approved medication KIMMTRAK® (tebentafusp-tebn; FDA approved in 2022).
2. Bulek et al (2012) Structural basis of human beta-cell killing by preproinsulin-specific CD8+ T-cells in type 1 diabetes. Nature Immunology 13, 283-289. This study included the first ever structure of a killer T-cell autoimmune T-cell receptor in complex with its cognate autoantigen. Subject News & Views article “Motifs for a deadly encounter” Nature Immunology 13, 197-198.
3. Cole et al (2016) Hotspot autoimmune T-cell receptor binding to pathogen and insulin peptides. Journal of Clinical Investigation, 126, 2191-204. This paper features on the journal cover (June 2016 issue) and is subject of feature article “A ‘hotspot’ for autoimmune T cells in type 1 diabetes”. The article also featured at over 200 media outlets.
4. Hanson et al (2016) Reversible oligonucleotide chain blocking enables bead capture and amplification of T-cell receptor alpha and bets chain mRNAs. Journal of the American Chemical Society, 138, 11073-6. This article received the journal cover and was featured as a “Spotlight”. It was also featured at the “Research Highlight” in the October 2016 issue of Nature Methods 13:816.
5. Maciocia et al (2017) Targeting T-cell receptor β-constant region for immunotherapy of T-cell malignancies. Nature Medicine, 23, 1416-1423. This paper was the subject of News & Views article “Targeted cellular immunotherapy for T cell malignancies” Nature Medicine 23, 1402-03. Subject of Nature Reviews Drug Discovery Research Highlight “Cancer: Strategies for mature T-cell cancers” (volume 17, page 15). Subject of “Target therapies: Strategies for mature T cell cancers Nature Reviews Cancer 18 page 3. Featured by various scientific and general media outlets including the BBC. Approach now in clinical trial as a CAR-T therapy via Autolus.
6. Legut et al (2018) CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. Blood, 131, 311-322. Subject of commentary entitled: “Editing gene engineering to enhance function” Blood 131, 272-273. Featured by various media outlets including the BBC. TCR replacement has now been used safely in the clinic.
7. Shugay et al (2018). VDJdb - a curated database of T-cell receptor sequences with known antigen specificity. Nucleic Acid Research, 46, D419-D427 doi: 10.1093/nar/gkx760. Rated “exceptional” by Faculty of 1000. Listed as highly cited by the Institute of Scientific Indexing (see https://vdjdb.cdr3.net)
8. Miles, Dolton et al (2018) Peptide Mimic for Influenza Vaccination Using Non-natural Combinatorial Chemistry. Journal of Clinical Investigation, 128, 1569-80. This paper got the journal cover and was the subject of a feature article “Synthetic peptides mirror vaccine efficacy and enhance biological stability” It was also featured by the BBC, Newsweek, The Times, The independent etc. Featured as Research Highlight “The peptide D-list” Nature Chemical Biology, 14, 413-4.
9. Crowther, Dolton et al (2020) Genome-wide CRISPR-Cas9 Screening Reveals Ubiquitous T-cell Cancer Targeting via the monomorphic MHC class I related protein MR1. Nature Immunology, 21, 178-185. >100,000 downloads. Top 80 Altmetric score of 2020 and highest scoring cancer paper https://www.nature.com/articles/s41590-019-0578-8/metrics
10. Dolton, Rius, Hasan, Wall et al (2022). Emergence of immune escape at dominant SARS-CoV-2 killer T-cell epitope (2022). Cell, 16, 2936-2951. This work allowed us to keep the lab open during the extensive COVID lockdown in Wales