Development of Adoptive immunotherapy of EBV-associated Malignancies by Retroviral LMP2-TCR Gene Transfer

Lead Research Organisation: University College London
Department Name: Infection

Abstract

Epstein Barr Virus (EBV) can cause several different types of cancer. There are currently no treatments available for some of these cancers. Our proposal is to take blood cells from patients with EBV-associated cancer and turn them into killer cells directed towards the cancer cells and then inject back into the patient. These killer cells will then be able to destroy the cancer cells and cure the patient.

Technical Summary

Latent membrane protein-2 (LMP2) is an Epstein Barr Virus (EBV)-derived antigen that is expressed in approximately 40% of lymphomas, 10% gastric carcinomas and virtually all undifferentiated non-keratinising nasopharyngeal carcinomas (NPC) with poor prognosis. We propose to develop T cell receptor (TCR) gene therapy to generate LMP2-specific T cell populations for the treatment of EBV-associated lymphomas, gastric cancer and NPC. We have recently isolated the genes encoding the alpha and beta chain of a high avidity LMP2-specific TCR. The aim of the project will be to demonstrate that TCR-gene transfer efficiently generates LMP2-specific CD4+ and CD8+ T cell populations that are capable recognising tumour cells expressing LMP2 endogenously. Successful completion of the project will form the basis of a Phase I/II clinical trial in patients.

Publications

10 25 50
 
Description Centre Grant
Amount £2,418,108 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2010 
End 01/2015
 
Description Clinical Training Fellowship
Amount £230,607 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Clinical Training Fellowship
Amount £253,094 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description MRC DPFS
Amount £256,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2010 
End 07/2012
 
Description Program Grant
Amount £1,895,702 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2008 
End 10/2013
 
Title Gene engineered T cells 
Description The function of gene modified T cells was enhanced by co-transfer of TCR and single chain FV constructs to mediate co-stimulation. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact The developed technology may enhance the efficacy and specificity of TCR gene therapy 
 
Title LMP2-TCR 
Description TCR genes validated. Next step is a clinical trial. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The TCR genes have been patented 
 
Description ATTRACT 
Organisation University of Manchester
Department School of Medicine Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide research and training expertise
Collaborator Contribution This is an EU funded project coordinated from Manchester
Impact appointment of a PhD student
Start Year 2009
 
Description Immunotherapy in NSG mice 
Organisation University of Zurich
Department Institute of Experimental Immunology
Country Switzerland 
Sector Academic/University 
PI Contribution In this collaboration, we explore T Cell therapy of EBV tumors. We provide the T Cell expertise/reagents and Prof. Munz the animal model.
Collaborator Contribution Zurich provides expertise in the NSG animal model.
Impact Grant application to LLR.
Start Year 2012
 
Description Wuerzburg Collaboration 
Organisation University of Wurzburg
Department Department of Haematology
Country Germany 
Sector Academic/University 
PI Contribution We have isolated the TCR genes that are used in this project
Collaborator Contribution Provision of cells used for TCT cloning
Impact Our collaborator Prof Topp is co-applicant on this grant
Start Year 2009
 
Title LMP2-TCR 
Description The LMP2-TCR may be used for TCR gene therapy of lymphoma and nasopharyngeal carcinoma. A patent has been filed for the theurapeutic exploitation of the LMPC-TCR. 
IP Reference WO2011039508 
Protection Patent application published
Year Protection Granted 2009
Licensed No
Impact Strong platform for commercial interactions
 
Title Trial re-opened to recruitment after long delay. 3rd Qp released GMP product manufactured and patient dosed. 
Description TCR gene modified allogeneic T cells, currently being evaluated in a phase I clinical trial. Funding to date has been MRC and NIHR BRC (UCLH/UCL) 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Actively seeking support
Clinical Trial? Yes
Impact first use of gene-modified allogeneic T cells in EU 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-006649-18
 
Description Public Lecture on T Cell therapy. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Approximately 200 lay people attended lecture on T Cell therapy.

Lecture was recorded and is available on You-tube.
Year(s) Of Engagement Activity 2010,2012
URL http://www.youtube.com/watch?v=uVJu3RJ1QSk
 
Description School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Parents attended the presentation which was followed by a lively discussion, and some individuals wanting to donate money for research.

School asked me to come back for a second presentation.
Year(s) Of Engagement Activity 2010
 
Description School Visit Primrose Hill 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Parents attended a presentation of our research and all children attended an assembly

Children raised funds to support cancer research
Year(s) Of Engagement Activity 2010,2011