Cellular immunotherapies such as chimeric antigen receptor T-cell (CAR-T) have proved revolutionary in haematological malignancy, effecting cures in otherwise unsalvageable cancers. However, not all patients benefit, especially outside the non-Hodgkin lymphoma setting and the expansion of their use is complicated by potentially life-threatening toxicity.
CAR-T cell therapy is a revolutionary new cancer treatment that involves engineering a patient’s immune cells to help them attack the tumour more effectively. They are highly effective for certain types of cancer, but It is not clear why side-effects are severe in some patients and mild or non-existent in others, although it likely relates to differences in immune systems between individuals. We are using new technologies to help us better understand the immune system and to investigate how and why toxicity develops. We will use this knowledge to design interventions that make CAR-T therapy safer and more widely available.
A major reason for failure of CAR T-cell therapy is inappropriate antigenic target. Our lab is applying cutting edge cell surface proteomic techniques to map the cell surface of cancer cells. We have developed algorithms to leverage these data which we are using to identify novel immunotherapeutic targets and develop new CAR T-cell therapies.
Publications
Quintas A, Harvey RF, Horvilleur E, Garland GD, Schmidt T, Kalmar L, Dezi V, Marini A, Fulton AM, Pöyry TAA, Cole CH, Turner M, Sawarkar R, Chapman MA, Bushell M, Willis AE. Eukaryotic initiation factor 4B is a multi-functional RNA binding protein that regulates histone mRNAs. Nucleic Acids Res. 2024 Oct 28;52(19):12039-12054. doi: 10.1093/nar/gkae767.
Anderson GSF, Chapman MA. T cell-redirecting therapies in hematological malignancies: Current developments and novel strategies for improved targeting. Mol Ther. 2024 Sep 4;32(9):2856-2891. doi: 10.1016/j.ymthe.2024.07.028.
Takahashi M, So TY, Chamberlain-Evans V, Hughes R, Yam-Puc JC, Kania K, Ruhle M, Mann T, Schuijs MJ, Coupland P, Naisbitt D, Halim TYF, Lyons PA, Lio P, Roychoudhuri R, Okkenhaug K, Adams DJ, Smith KGC, Jodrell DI, Chapman MA, Thaventhiran JED. Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site. Sci Immunol. 2024 May 24;9(95):eade2094. doi: 10.1126/sciimmunol.ade2094.
Walker IG, Roy JP, Anderson GSF, Guerrero Lopez J, Chapman MA. Targeting myeloma essential genes using NOT Gated CAR T-cells, a computational approach. Leukemia. 2024 Aug;38(8):1848-1852. doi: 10.1038/s41375-024-02247-1.
Yam-Puc JC, Hosseini Z, Horner EC, Gerber PP, Beristain-Covarrubias N, Hughes R, Lulla A, Rust M, Boston R, Ali M, Fischer K, Simmons-Rosello E, O'Reilly M, Robson H, Booth LH, Kahanawita L, Correa-Noguera A, Favara D, Ceron-Gutierrez L, Keller B, Craxton A, Anderson GSF, Sun XM, Elmer A, Saunders C, Bermperi A, Jose S, Kingston N, Mulroney TE, Piñon LPG; CITIID-NIHR COVID−19 BioResource Collaboration; Chapman MA, Grigoriadou S, MacFarlane M, Willis AE, Patil KR, Spencer S, Staples E, Warnatz K, Buckland MS, Hollfelder F, Hyvönen M, Döffinger R, Parkinson C, Lear S, Matheson NJ, Thaventhiran JED. Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade. Nat Commun. 2023 Jun 27;14(1):3292. doi: 10.1038/s41467-023-38810-0.
Pereira C, Stalder D, Anderson GSF, Shun-Shion AS, Houghton J, Antrobus R, Chapman MA, Fazakerley DJ, Gershlick DC. The exocyst complex is an essential component of the mammalian constitutive secretory pathway. J Cell Biol. 2023 May 1;222(5):e202205137. doi: 10.1083/jcb.202205137.
Parol W, Anderson GSF, Chapman MA. CAR-T cell therapies for cancer: what novel technologies are being developed for toxicity data? Expert Opin Drug Metab Toxicol. 2022 Apr;18(4):241-244. doi: 10.1080/17425255.2022.2085551.
Anderson GSF, Ballester-Beltran J, Giotopoulos G, Guerrero JA, Surget S, Williamson JC, So T, Bloxham D, Aubareda A, Asby R, Walker I, Jenkinson L, Soilleux EJ, Roy JP, Teodósio A, Ficken C, Officer-Jones L, Nasser S, Skerget S, Keats JJ, Greaves P, Tai YT, Anderson KC, MacFarlane M, Thaventhiran JE, Huntly BJP, Lehner PJ, Chapman MA.Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma. Blood. 2022 Apr 21;139(16):2471-2482. doi: 10.1182/blood.2021015161.
Chapman MA, Sive J, Ambrose J, Roddie C, Counsell N, Lach A, Abbasian M, Popat R, Cavenagh JD, Oakervee H, Streetly MJ, Schey S, Koh M, Willis F, Virchis AE, Crowe J, Quinn MF, Cook G, Crawley CR, Pratt G, Cook M, Braganza N, Adedayo T, Smith P, Clifton-Hadley L, Owen RG, Sonneveld P, Keats JJ, Herrero J, Yong K. RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature. Blood. 2018 Nov 15;132(20):2154-2165. doi: 10.1182/blood-2018-05-849893.
Januszkiewicz AJ, Bazar MA, Crouse LCB, Chapman MA, Hodges SE, McCormick SJ, O'Neill AJ. Morbidity and mortality resulting from acute inhalation exposures to hydrogen fluoride and carbonyl fluoride in rats. Inhal Toxicol. 2018 Feb;30(3):114-123. doi: 10.1080/08958378.2018.1465494.
Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, Sougnez C, Knoechel B, Gould J, Saksena G, Cibulskis K, McKenna A, Chapman MA, Straussman R, Levy J, Perkins LM, Keats JJ, Schumacher SE, Rosenberg M; Multiple Myeloma Research Consortium; Getz G, Golub TR. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014 Jan 13;25(1):91-101. doi: 10.1016/j.ccr.2013.12.015.
Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM, Onofrio R, Pugh TJ, Rajkumar SV, Ramos AH, Siegel DS, Sivachenko A, Stewart AK, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn WC, Garraway LA, Meyerson M, Lander ES, Getz G, Golub TR. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011 Mar 24;471(7339):467-72. doi: 10.1038/nature09837.
Chapman MA, Donaldson IJ, Gilbert J, Grafham D, Rogers J, Green AR, Göttgens B. Analysis of multiple genomic sequence alignments: a web resource, online tools, and lessons learned from analysis of mammalian SCL loci. Genome Res. 2004 Feb;14(2):313-8. doi: 10.1101/gr.1759004.
Chapman MA, Charchar FJ, Kinston S, Bird CP, Grafham D, Rogers J, Grützner F, Graves JA, Green AR, Göttgens B. Comparative and functional analyses of LYL1 loci establish marsupial sequences as a model for phylogenetic footprinting. Genomics. 2003 Mar;81(3):249-59. doi: 10.1016/s0888-7543(03)00005-3.
Göttgens B, Barton LM, Chapman MA, Sinclair AM, Knudsen B, Grafham D, Gilbert JG, Rogers J, Bentley DR, Green AR. Transcriptional regulation of the stem cell leukemia gene (SCL)--comparative analysis of five vertebrate SCL loci. Genome Res. 2002 May;12(5):749-59. doi: 10.1101/gr.45502.
