T cell therapy for human cancers
Antibodies for cancer therapy are already in clinical use, but T cells offer even greater potential in this context because of their ability to recognise intracellular antigens. Our laboratory is seeking to develop T cell therapy for human cancer by focussing on those tumours that carry the Epstein-Barr virus (EBV), a known target for the T cell response. Lessons learnt from this work are then being applied to develop effective T cell therapy for more common non-virus associated malignancies including renal cell carcinoma.
Through a well established collaboration with the Chinese University of Hong Kong (Prof. A.T.C. Chan, Prof. K.W. Lo) we are investigating T cell responses to the undifferentiated form of Nasopharyngeal carcinoma (NPC), one of the most common cancers in South East Asia and one that is consistently EBV-positive. Alongside our basic research into the immunology of this cancer, including the definition of viral target antigens, immune evasion mechanisms and the function of T cells that naturally reside within the tumour tissue, we are developing adoptive T cell therapy approaches.
T cell receptor gene transfer - Having established the use of adoptive T cell therapy in Birmingham through a pilot study in which 6 cancer patients were safely infused with tumour antigen-specific T cell clones, we are currently developing a rapid and reliable approach to generate therapeutic T cells using T cell receptor (TCR) gene transfer. We have successfully cloned a gene encoding a TCR specific for LMP2, an EBV protein widely expressed in NPC. Using retroviral mediated gene transfer we have then delivered this TCR into T cells. The result is that within 3-5 days we can reliably generate large numbers of high avidity LMP2-specific effectors capable of recognising cells endogenously expressing physiological levels of this viral protein. We are currently designing a phase I trial in which to test these modified T cells in NPC patients.
Chimeric antigen receptors - More recently, we are exploring another approach to engineer T cells for cancer therapy by transducing genes encoding so-called “chimeric antigen receptors” (CARs). CARs combine the specificity of antibodies with the cytotoxic and immunomodulatory functions of T cells and function in an MHC-unrestricted manner. Typically, CARs consist of a single chain variable fragment (scFv) of a specific antibody linked to intracellular T cell signalling domains. In a project recently funded by Cancer Research UK, we shall develop CARs to target a newly described C-type lectin CLEC14A. Work from our collaborator Prof Roy Bicknell (University of Birmingham) has demonstrated that CLEC14A is highly expressed on the surface of endothelial cells lining the vasculature of many common human cancers but is poorly expressed/undetectable in the vasculature of healthy tissue. In this way we aim to target a patient’s T cells to selectively destroy the tumour vasculature upon which the survival and growth of a tumour depends.
T cell recruitment to tumour tissue - If T cells are to be effective in treating cancer, they must be capable of homing to the tumour site. But they will only be recruited to a tissue if they express the appropriate selectins, integrins and chemokine receptors for engaging molecules presented at this site. Since many tumours (e.g. NPC, Hodgkin’s lymphoma and Renal cell carcinoma) are naturally infiltrated with T cells, another key area of our research is to define the mechanisms whereby these cells are recruited with a view to conferring the appropriate homing phenotype on tumour-specific effectors.
Parsonage G, Machado LR, Hui J, McLarnon A, Schmaler T, Balasothy M, To K-F, Vlantis AC, van Hasselt CA, Lo KW, Wong W-L, Hui EP, Chan A and Lee SP (2012) CXCR6 and CCR5 localise T lymphocyte subsets in Nasopharyngeal Carcinoma. Am J Pathol. 180, 1215-22.
Oldham KA, Parsonage G, Bhatt RI, Wallace DMA, Deshmukh N, Chaudhri S, Adams DH and Lee SP (2012) T lymphocyte recruitment into Renal Cell Carcinoma tissue: A role for chemokine receptors CXCR3, CXCR6, CCR5 and CCR6. Eur Urol. 61, 385-394.
Dowell AC, Oldham KA, Bhatt RI, Lee SP and Searle PF. Long-term proliferation of functional human NK cells, with conversion of CD56dim NK cells to a CD56bright phenotype, induced by carcinoma cells co-expressing 4-1BBL and IL-12. Cancer Immunol. Immunother. In press.
Fox CP, Haigh TA, Taylor GS, Long HM, Lee SP, Shannon-Lowe C, O'Connor S, Bollard CM, Iqbal J, Chan WC, Rickinson AB, Bell AI, Rowe M (2010) A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK and T cell lymphoproliferative disease encodes a target for cellular immunotherapy. Blood. 116, 3695-3704.
Long, H.M., G. Parsonage, C.P. Fox and S.P. Lee. 2010. Immunotherapy for Epstein-Barr virus-associated malignancies. Drug News Perspect. 23. 221-228.
Brooks, JM, Lee SP, Leese AM, Thomas WA, Rowe M and Rickinson AB (2009) Cyclical Expression of EBV Latent Membrane Protein 1 in EBV-Transformed B Cells Underpins Heterogeneity of Epitope Presentation and CD8+ T Cell Recognition. J Immunol. 182, 1919–1928.
Machado, L, Jarrett R, Morgan S, Murray P, Hunter B, Crocker J, Thomas W, Steven N, Ismail T, Chapman A, Adams D, Lee S (2009) Expression and function of T cell homing molecules in Hodgkin’s Lymphoma. Cancer Immunol. Immunother. 58, 85-94.
Baumforth, KRN, A Birgersdotter, GM Reynolds, W Wei, G Kapatai, JR Flavell, E Kalk, K Piper, S Lee, L Machado, K Hadley, A Sundbland, J Sjoberg, M Bjorkholm, AA Porwit, LF Yap, S Teo, RG Grundy, LS Young, I Ernberg, CBJ Woodman and PG Murray (2008) Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells. Am J Pathol. 173, 195-204.
Hart, DP, Xue S-A, Thomas S, Cesco-Gaspere M, Tranter A, Willcox B, Lee SP, Steven N, Morris EC and Stauss HJ (2008) Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells. Gene Ther. 15, 625-31.
Onion, D, Crompton LJ, Milligan DW, Moss PAH, Lee SP and Mautner V (2007) The CD4+ T-cell response to adenovirus is focussed against conserved residues within the hexon protein. J Gen Virol. 88, 2417-2425.
Lau, KM, Cheng SH, Lo KW, Lee SA, Woo JK, van Hasselt CA, Lee SP, Rickinson AB and Ng MH (2007) Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients. Br J Cancer. 96, 617-622
Schaft, N, Lankiewicz B, Drexhage J, Berrevoets C, Moss DJ, Levitsky V, Bonneville M, Lee SP, McMichael AJ, Gratama JW, Bolhuis RLH, Willemsen R and Debets R (2006) T cell re-targeting to EBV antigens following TCR gene transfer: CD28-containing receptors mediate enhanced antigen-specific IFNγ production. Int. Immunol. 18, 591-601