UCL Cancer Institute


Tumour Immunology, Cellular and Gene Therapy


PIs: Prof Hans Stauss, Dr Emma Morris, Dr Shao-An Xue


Our group is located in the newly developed Institute of Immunity, Infection and Transplantation at the Royal Free campus.

Summary

Our work predominantly focuses on the cellular immunotherapy and gene therapy of cancer and infection. This ranges from basic science projects (in vitro and in vivo) exploring T cell avidity, function and tolerance, including the development of pre-clinical animal models through to first-in- man Phase I Investigator-led studies of genetically modified T cells for immunotherapy through to extended Phase II and Phase III studies of novel conditioning regimens for allogeneic haematopoietic stem cell transplantation and cellular therapies. We use gene transfer technologies to alter the function and/or specificity of T cells to improve anti-tumour immunity.


PhD Projects

  • Novel approaches for generation of antigen-specific T cells for leukaemia and cancer immunotherapy.
  • Retroviral gene transfer of T cell receptor (TCR) genes into T cells and haematopoietic stem cells to re-direct antigen-specificity and explore mechanisms of tolerance to self-reactive T cells.
  • The generation of MHC class I-restricted tumour antigen-specific CD4+ helper T cells to augment CD8+ T cell mediated tumour immunotherapy.
  • Analysis of functional avidity and signaling pathways of tumour antigen-specific TCRs.
  • Investigation of the role of the CD8 co-receptor in TCR transduced CD4+ helper T cells and conventional CD8+ T cells.
  • Augmenting the effector function of Ag-specific T cells by the introduction of additional CD3 molecules.
  • The generation of pre-clinical models for the evaluation of WT1-specific immunotherapy (WT1 is a tumour associated antigen over-expressed in myelodysplasia (MDS), leukaemias (AML, CML), breast, ovarian, prostate and colon cancers.
  • Isolation of TCRs from T cell clones specific for tumour antigens.
  • Generation of antigen-specific regulatory T cells using TCR gene transfer in murine models of Graft-versus-Host Disease.
  • The genetic manipulation of T cells to improve homing to tumour sites and/or persistence in the hostile tumour microenvironment.
  • The development of clinical GMP grade transduction protocols for the genetic manipulation of T cells for clinical use.
  • The interaction of tumour-specific T cells and tumour associated macrophages.


Translational Clinical Research

  • Immune monitoring in recipients of renal and liver transplants
  • WT1 TCR Gene Therapy for leukaemia: A Phase I safety and toxicity clinical trial
  • CMV TCR Gene Therapy: A Phase I Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy in Allo-HSCT

isolation

Fig 1   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.



retroviral gene transfer

Fig 2   Schematic representation of retroviral gene transfer to redirect antigen specificity.



GROUP MEMBERS


Professor Hans Stauss MD PhD
EmailIRIS
UCLP Immunology & Transplantation
Division of Infection & Immunity

Dr Emma Morris PhD, MRCP, MRCPath, Reader
EmailIRIS
Division of Infection & Immunity

Dr Shao-An Xue PhD, Senior Lecturer
EmailIRIS
Division of Infection & Immunity

Dr Liquan Gao MD, Senior Research Fellow
Email,   IRIS

Mrs Eira Rawlings MSc HND, Laboratory Manager
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Dr Maryam Ahmadi PhD, Postdoctoral Scientist
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Ms Lyn Ambrose MSc, Research Technician
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Dr Ben Carpenter MBBS, PhD Student
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Dr Ignatius Chua MB BS, PhD Student
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Dr Sara Ghorashian MBBS, PhD Student
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Mr David Guzman Lic, Database Manager/Developer
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Ms Angelika Holler MSc, Research Technician
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Dr Irma Martinez-Davila PhD, Postdoctoral Scientist
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Dr Emma Nicholson MBBS, PhD Student
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Dr Rebecca Pike PhD, Research Technician
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Dr Maria Serrano PhD, Clinical Trial Coordinator
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Ms Maria Stavrou MSc, UCL Grand Challenges PhD Student
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Dr Sharyn Thomas PhD, Postdoctoral Scientist
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Dr Ben Uttenthal MBBS, PhD Student
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Mrs Jennifer Wanders MSc, Research Technician
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Selected Recent Publications


CD3 limits the efficacy of TCR gene therapy in vivo. Ahmadi M, King JW, Xue SA, Voisine C, Holler A, Wright GP, Waxman J, Morris E, Stauss HJ. Blood. 2011 Sep 29;118(13):3528-37.

Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen. Thomas S, Xue SA, Bangham CR, Jakobsen BK, Morris EC, Stauss HJ. Blood. 2011 Jul 14;118(2):319-29.

Specificity for the tumor-associated self-antigen WT1 drives the development of fully functional memory T cells in the absence of vaccination. Pospori C, Xue SA, Holler A, Voisine C, Perro M, King J, Fallah-Arani F, Flutter B, Chakraverty R, Stauss HJ, Morris EC. Blood. 2011 Jun 23;117(25):6813-24.

Generation of multi-functional antigen-specific human T-cells by lentiviral TCR gene transfer. Perro M, Tsang J, Xue SA, Escors D, Cesco-Gaspere M, Pospori C, Gao L, Hart D, Collins M, Stauss H, Morris EC. Gene Ther. 2010 Jun;17(6):721-32.

Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Wright GP, Notley CA, Xue SA, Bendle GM, Holler A, Schumacher TN, Ehrenstein MR, Stauss HJ. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19078-83.

Development of a Wilms' tumor antigen-specific T-cell receptor for clinical trials: engineered patient's T cells can eliminate autologous leukemia blasts in NOD/SCID mice. Xue SA, Gao L, Thomas S, Hart DP, Xue JZ, Gillmore R, Voss RH, Morris E, Stauss HJ. Haematologica. 2010 Jan;95(1):126-34.