Dr Emma Morris -
• Novel approaches to antigen-specific T cell therapies
• TCR Gene Therapy
• Clinical translation and Phase I trials

Other group members ->

Active Research Projects

Currently, the following translational and basic research projects are performed in the Tumour Immunology Research Group:

• A clinical phase I/II peptide vaccination trial in leukaemia patients

• Construction and validation of retroviral vectors suitable for clinical TCR gene therapy trials in patients with leukaemia and solid tumours

• Construction and validation of lentiviral vectors for TCR gene transfer

• Analysis of local and systemic T cell responses against tumour-associated antigens in patients with leukaemia and solid tumours

• In vivo analysis of TCR gene modified T cells in murine models: mechanisms of CD4 and CD8 T cell interaction, T cell migration, survival and memory development.

• Production of modified TCRs to prevent pairing with endogenous TCRs

• Mapping TCR domains dictating T cell effector function

• Assessing the functional activity of TCRs that were affinity matured in vitro by phage display

• Analysis of tolerance mechanisms in a TCR transgenic murine model

• Use of dendritic cell vaccination strategies in murine models

Fig1. The isolation of tumour antigen-specific cytotoxic T lymphocytes (CTL) from healthy donors is labour intensive (1). Molecular cloning techniques facilitate the isolation of genes encoding the TCR alpha and beta chains, which determine T cell specificity. Retroviral gene transfer permits the introduction of these tumour-specific TCR genes into patient T cells, via ex vivo retroviral infection (2). In this way, patient T cells can be equipped with anti-tumour specificity, which may be lacking from their self-restricted repertoire. The TCR-transduced T cells are then returned to the patient following lymphodepleting conditioning therapy (3).

Fig2. Schematic representation of retroviral gene transfer to redirect antigen specificity.

Fig3. Surface expression of pWT126-specific TCR on transduced primary human lymphocytes was demonstrated by tetramer binding (HLA-A2/pWT126 tetramers) of CD8+ T cells. The TCR-transduced T cells displayed equivalent avidity to the parental CTL clone as determined by cytotoxicity against peptide loaded T2 target cells.

Fig4. TCR transduced T cells of a patient with CML are able to kill T2 cells coated with pWT126 (pWT235 served as a control) and the A2+WT1+ leukaemia line BV173, whilst T cells from the same patient transduced with an irrelevant TCR failed to kill any of these targets.

Fig5. Immunodeficient NOD/SCID mice were inoculated i.v. with 5 x 106 BV173 leukaemia cells, and the following day 20 x 106 TCR-transduced T cells or control TCR-transduced T cells were injected i.v. After 3 weeks mice were sacrificed and the number of leukaemia cells in the bone marrow and spleen (not shown) was determined.

Fig6. Bone marrow cells from the experiment described in Figure 5 were stained with anti-human HLA class I, anti-CD45 and anti CD8 and analysed using a FACSCalibur. Shown is the HLA class I and CD45 staining of bone marrow cells treated with control TCR-transduced T cells (upper row) and WT1 TCR-transduced T cells (lower row).

E. Morris, D. Hart, Liquan Gao, A. Tsallios, S. Xue, Hans Stauss. Generation of tumor-specific T-cell therapies. Blood Reviews. 2006 20(2):61-9. (PubMed)

Morris EC, Tsallios A, Bendle GM, Xue SA, Stauss HJ. A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection. Proc Natl Acad Sci USA. 2005 102(220):7934-9. (PubMed)

Xue S A, Gao L, Hart D, Gillmore R, Waseem Q, Thrasher A, Apperley J, Engels B, Uckert W, Morris E, Stauss H. Elimination of human leukaemia cells in NOD/SCID mice by WT1-TCR gene transduced human T cells. Blood. 2005 106 (9):3062-7. (PubMed)

S. Xue, R. Gillmore, A. Downs, A. Tsallios, A. Holler, L. Gao, V. Wong, E. Morris and H.J. Stauss. Exploiting TCR Genes for Cancer Immunotherapy. Clin Exp Immunol. 2005 Feb;139(2):167-72. (PubMed)

G. Bendle, A. Holler, L. Pang, S. Hsu, M. Krampera, E. Simpson, E. Sadovnikova and H.J. Stauss. Induction of unresponsiveness limits tumor protection by adoptively transferred MDM2-specific cytotoxic T lymphocytes. Cancer Research 2004 Nov 1;64(21):8052-6. (PubMed)

Savage, L. Gao, K.Vento, P. Cowburn, S. Man, N. Steven, G. Ogg, A. McMichael, A. Epenetos, E. Goulmy and H.J. Stauss. Use of B-cell bound HLA-A2 class I monomers to generate high avidity, allo-restricted CTL against the leukemia-associated protein Wilms tumor antigen 1. (2004) Blood, (2004) Jun 15;103(12):4613-5. (PubMed)

F. Ramírez, Y. Ghani and H.J. Stauss. Incomplete tolerance to the tumour-associated antigen MDM2 (2003) International Immunology, (2004) Feb;16(2):327-34 (PubMed)

Gao, L., Xue, S., Hasserjian, R., Cotter, F. Kaeda, J. Goldman, J.M., Dazzi, F. and Stauss, H.J. Human cytotoxic T-lymphocytes specific for Wilms tumor antigen-1 inhibit engraftment of leukemia-initiating stem cells in NOD/SCID recipients. (2003) Transplantation, 75:1429-36. (PubMed)

P. Amrolia, S. D. Reid, L. Gao, B. Schultheis, G. Dotti, M. K. Brenner, J. V. Melo, J. M. Goldman and H. J. Stauss. Allo-restricted cytotoxic T-cells specific for human CD45 show potent anti-leukemic activity. (2003) Blood, Feb 1;101(3):1007-14. (PubMed)

I.Bellantuono, L.Gao, S. Parry, S. Marley, F.Dazzi^, J. Apperley, J.M. Goldman and H.J. Stauss. Two distinct HLA-A0201-presented epitopes of the Wilms Tumor Antigen 1 can function as targets for leukemia-reactive CTL. (2002) Blood. Nov 15;100(10):3835-7. (PubMed)

E. Sadovnikova, E.N. Parovichnikova, V.G. Savchenko, T. Zabotina and H.J. Stauss. The CD68 protein as a potential target for leukaemia-reactive CTL" (2002) Leukemia, Oct;16(10):2019-26. (PubMed)

T.H.Yang, M. Lovatt, M. Merkenschlager and H.J. Stauss. Comparison of the frequency of peptide-specific CTL restricted by self and allo-MHC following in vitro T cell priming. (2002) International Immunology, Nov;14(11):1283-90 (PubMed)

Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J, Ruppert T, Bolhuis RL, Melief CJ, Huber C, Stauss HJ, Theobald M. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. (2001) Nature Immunology Oct;2(10):962-70. (PubMed)

Gao, L., Bellantuono, I., Elsaesser, A., Marley, S., Gordon, M.Y., Goldman, J.M. and Stauss, H.J. "Selective elimination of leukaemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1". Blood 95 (2000) 2198-203 (plenary paper) (PubMed)