T-cells are a vital component of the immune system and promoting/engineering T-cell responses is now at the forefront of cancer immuno-therapies. The ability of a T-cell to display full effector functions (e.g. proliferation, cytotoxicity) crucially depends on optimal cellular energy utilisation and the availability of nutrients in the environment. Cancer cells’ ferocious uptake of nutrients can outcompete T-cells, inhibiting their immune response and leading to treatment failure. Novel CAR constructs aim to genetically optimise the metabolic profile of therapeutic T-cells to withstand this challenge. To improve CAR-T cell function by targeting cellular metabolic programming, we will here investigate the most promising pathways. As a PhD student with us you will be utilising recently established novel in-vitro culture systems to mimic the tumour microenvironment, allowing for detailed study of T-cell/tumour cell interaction in nutrient/oxygen-controlled conditions. In the first year you will gain in depth knowledge in human T-cell/cancer biology and immunometabolism, learning how to produce, culture and metabolically assess human CAR T-cells. You will receive training in advanced flowcytometry and high-resolution imaging for single cell functional and metabolic analysis. In the second phase you will verify that identified mechanisms play a role in-vivo by assessing CAR-T cells harvested after adoptive transfer from murine models. Depending on your findings, the study can be extended to patient-derived CAR-T cells, through our close clinical collaborations. You will undertake computational training for additional interrogation of publicly available datasets. Finally, you will use your knowledge to modify and validate your CAR platform, thus you will gain an understanding of how to genetically engineer T-cells. This project is highly translational and your research has the potential to contribute to clinical trials. AS’s and JM’s groups are working closely together and we are located in the same building, facilitating exchange.
Understanding metabolic challenges impacting Chimeric antigen receptor (CAR) T cell function
Shared by both supervisors: Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors. Muliaditan T, Halim L, Whilding LM, Draper B, Achkova DY, Kausar F, Glover M, Bechman N, Arulappu A, Sanchez J, Flaherty KR, Obajdin J, Grigoriadis K, Antoine P, Larcombe-Young D, Hull CM, Buus R, Gordon P, Grigoriadis A, Davies DM, Schurich A, Maher J. Cell Rep Med. 2021 Dec 21;2(12):100457. doi: 10.1016/j.xcrm.2021.100457. eCollection 2021 Dec 21. PMID: 35028604 Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells. Sanchez J, Jackson I, Flaherty KR, Muliaditan T, Schurich A. Metabolites. 2020 Nov 13;10(11):461. doi: 10.3390/metabo10110461. PMID: 33202938 The Metabolic Profile of Tumor and Virally Infected Cells Shapes Their Microenvironment Counteracting T Cell Immunity. Magalhaes I, Yogev O, Mattsson J, Schurich A. Front Immunol. 2019 Oct 4;10:2309. doi: 10.3389/fimmu.2019.02309. eCollection 2019. PMID: 31636636 Review.
Muliaditan T,* Halim L, *Whilding LM,* Draper B,* Achkova DY,* Kausar F,* Glover M,* Bechman N, Arulappu A, Sanchez J, Flaherty KR, Obajdin J, Grigoriadis K, Antoine P, Larcombe-Young D, Hull CM, Buus R, Gordon P, Grigoriadis A, Davies DM, Schurich A, Maher J (2021) Synergistic signaling by 41BB and CD28 in therapeutic T-cells is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors. Cell Reports Medicine. 2(12):100457 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00325-6 Halim L, Das KK, Larcombe-Young D, Ajina A, Candelli A, Benjamin R, Dillon R, Davies DM, Maher J (2022) Engineering of an avidity-optimized CD19-specific parallel chimeric antigen receptor that delivers dual CD28 and 4-1BB co-stimulation. Frontiers in Immunology. 13: 836549 https://doi.org/10.3389/fimmu.2022.836549 Papa S, Adami A, Metoudi M, Beatson R, George MS, Achkova D, WilliamsE, Arif S, Reid F, Elstad M, Beckley-Hoelscher N, Douri A, Delord M, Lyne M, Shivapatham D, Fisher C, Hope A, Gooljar S, Mitra A, Gomm L, Morton C, Henley-Smith R, Thavaraj S, Santambrogio A, Andoniadou C, Allen S, Gibson V, Cook GJR, Parente-Pereira AC, Davies DM, Farzaneh F, Schurich A, Guerrero-Urbano T, Jeannon JP, Spicer J, Maher J (2023) Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study. Journal for Immunotherapy of Cancer. 11(6) e007162 https://jitc.bmj.com/content/11/6/e007162