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Research Groups

CAR Group

Genetic targeting of T-cells against cancer using chimeric antigen receptors (CAR)

Group members

Overview

The most potent immunotherapy available for malignant disease is achieved when tumour-specific T-cells are administered to patients. This contributes vitally to the success of stem cell transplantation and donor leukocyte infusion for selected haematological malignancies.

A key obstacle to more widespread use of this treatment is the difficulty in generating large numbers of tumour-specific T-cells. To circumvent this, we are developing genetic strategies to re-direct T-cell specificity against target molecules found on common solid tumours. To achieve this, we use chimeric antigen receptor (CAR) technology.

"Research led by Dr John Maher, Senior Research Fellow in the Division of Cancer Studies, School of Medicine at King’s, has developed a new way for the body to detect and fight breast cancer."

CAR Structure

CARStructureThe structure of a typical CAR is shown here. These fusion receptors can be delivered to human T-cells using retroviral expression vector systems. Using this approach, we have re-directed T-cell reactivity against tumour cells that express PSMA, MUC1, CEA, ErbB2, the extended ErbB kinase family and the receptor for CSF-1

The accompanying images give an indication of what occurs when genetically targeted T-cells encounter antigen-expressing tumour cells. In this case, T-cells have been grafted with a MUC1-specific CAR named HOX and then mixed overnight with tumour. Upon contact with the tumour cells, the T-cells become highly activated and elicit rapid destruction of the tumour cell monolayer. The clumps that result contain a mixture of activated T-cells together with dead and dying cancer cells. Over the next 7 – 10 days, the T-cells proliferate leading to a 5 – 10 fold increase in T-cell number approximately. These T-cells can now be placed on a fresh tumour monolayer where the same process occurs once again. By contrast, none of these events result when control T-cells are mixed with tumour cells.

T47D1425w
T47D cell monolayer alone

T47D2425w
T47D cells plus HDF28zTrunc T cells (1x10e6 cells)

T47D3425w
T47D cells plus HDF28zOXz (HOX) T cells (1x10e6)

T47D4425w
T47D cells plus HDF28zOXz (HOX) T cells (1x10e6)

Recent publications

  • Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, Maher J (2008) Re-targeting of human T-cells to tumour-associated MUC1 – the evolution of a chimeric antigen receptor. Journal of Immunology 180: 4901-9. PubMed link
  • Lo A, Taylor J, Farzaneh F, Kemeny DM, Dibb NJ, Maher J (2008) Harnessing the tumour-derived cytokine, colony-stimulating factor-1, to co-stimulate T-cell growth and activation. Molecular Immunology 45: 1276-87. link
  • Lo AS, Gorak-Stolinska P, Bachy V, Ibrahim MA, Kemeny DM, Maher J (2007) Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3'-kinase and delayed caspase activation. Journal of Leukocyte Biology 82: 1446-54. PubMed link
  • Lo AS, Gorak-Stolinska P, Bachy V, Ibrahim MA, Kemeny DM, Maher J (2007) Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3'-kinase and delayed caspase activation. Journal of Leukocyte Biology 82: 1446-54. PubMed link
  • Maher J and Davies ET (2004). Targeting cytotoxic T-lymphocytes for cancer immunotherapy.  British Journal of Cancer 91, 817-821. PubMed link
  • Maher J (2002). Application of artificial T cell receptor technology to cancer immunotherapy (review). CPD Bulletin Immunology & Allergy (UK) 2: 89-91. PubMed link
  • Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M (2002) Human T lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR/ CD28 receptor. Nature Biotechnology 20: 70-75. PubMed link
  • Maher J (2002). Application of artificial T cell receptor technology to cancer immunotherapy (review). CPD Bulletin Immunology & Allergy (UK) 2: 89-91. 
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