The development of cellular therapy for the correction of CMV-specific immunodeficiency after stem cell transplantation

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

Bone marrow transplants (BMT) are commonly used to treat patients with leukaemia or inherited diseases of the bone marrow. Unfortunately, the procedure leaves patients with a very weakened immune system for a few months after transplant and they often suffer from severe infections. One of these is a virus called cytomegalovirus (CMV) which many of us carry but which rarely causes disease in healthy people.
We propose to study the details of how patients mount an immune response to CMV after BMT and to understand why some patients clear the infection whereas others get severe infection.
In addition we can now identify which patients are going to get severe disease and we are able to transfer immune cells from their transplant donor as a treatment. We now plan to optimise this treatment so that we deliver these cells at the most appropriate time and to the patients at greatest risk.
The work should lead to better control of CMV in our patients and will act as a model for the treatment of a wide range of serious infections in transplant patients.

Technical Summary

Allogeneic stem cell transplantation (SCT) is commonly used to treat malignant and inherited diseases of the bone marrow and involves replacing the bone marrow and haemopoietic system of a transplant patient with those of a donor. Unfortunately, the procedure continues to be complicated by an intense period of immunosuppression following transplantation which can lead to severe infectious complications. Cytomegalovirus (CMV) is a common pathogen in this setting and commonly leads to morbidity and mortality in SCT patients. Impaired cellular immunity to CMV leads directly to viral reactivation and approaches to correct this deficiency by directly infusing donor-derived CD8+ CMV-specific T cell clones which have been expanded in vitro have been reported.
My MRC Clinical Training Fellowship involved study of CMV-specific CD8+ T cell immune reconstitution in patients following SCT. I also initiated a phase I clinical trial in which CMV-specific CD8+ T cells are magnetically selected from the transplant donor and infused into the patient directly without ex vivo manipulation. Seven patients have currently been treated in what is the first clinical trial of this kind in the world.
In this application I wish to extend both of these studies in order to learn more about the determinants of the immune response to CMV and to optimise the cellular correction of CMV-specific immunotherapy. I propose to study the mechanisms that govern the functional activity of CMV-specific CTL post-SCT and to identify new CMV epitopes that may act as targets for immunotherapy. I plan to spend a year with Professor Victor Engelhard in North Carolina whose research group is the world leader in proteomic analysis of peptide epitopes. The second phase of the Fellowship application is concerned with the further development of clinical trials on the cellular correction of CMV-immunodeficiency. Specifically, I will address 3 issues - prophylactic rather than preemptive delivery of CD8+ CMV-specific T cells, the use of CD8+ CMV-specific T cells in the setting of unrelated donor transplantation and a trial of adoptive transfer of CD4+ CMV-specific CTL

This proposal offers the medical opportunity to develop novel approaches to the treatment of immunodeficiency following SCT and will have more general lessons for T cell immunotherapy.

Publications

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Chakupurakal G (2013) HLA-peptide multimer selection of adenovirus-specific T cells for adoptive T-cell therapy. in Journal of immunotherapy (Hagerstown, Md. : 1997)

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Nicholls S (2009) Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition. in Proceedings of the National Academy of Sciences of the United States of America

 
Description KKLF funding (Immune Targeting of the Phosphoproteome in Chronic Lymphocytic Leukaemia )
Amount £104,655 (GBP)
Organisation The Kay Kendall Leukaemia Fund 
Sector Academic/University
Country United Kingdom
Start 11/2008 
End 03/2011
 
Description Leukaemia Research (A randomised phase II trial of the adoptive transfer of tetramer selected cytomegalovirus-specific cytotoxic T lymphocytes (CMV-CTL) after allogeneic stem cell transplantation (SCT) in patients at risk of CMV disease)
Amount £624,180 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2012
 
Description Leukaemia Research (Characterising and immunologically targeting the phosphoproteome in acute myeloid leukaemia)
Amount £193,959 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2008 
End 11/2011
 
Description MRC Research Grant (Direct selection and adoptive transfer of allogeneic adenovirus-specific T lymphocytes to treat adenoviral infection following stem cell transplantation)
Amount £479,249 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2006 
End 04/2009
 
Description UHB Charities
Amount £70,000 (GBP)
Organisation Queen Elizabeth Hospital Birmingham Charity (QEHB) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2008 
End 09/2013
 
Title T cell lines 
Description Phosphopeptide-specific T cell lines. 
Type Of Material Cell line 
Year Produced 2008 
Provided To Others? Yes  
Impact Ongoing studies with Dr Ben Willcox 
 
Description MRC Centre for Immune Regulation 
Organisation University of Birmingham
Department MRC Centre for Immune Regulation
Country United Kingdom 
Sector Academic/University 
PI Contribution Member of MRC Centre
Collaborator Contribution Use of facilities and studentships.
Impact All outcomes from this application form.
 
Description Novartis 
Organisation Novartis Institutes for BioMedical Research (NIBR)
Department Novartis Vaccines Institute for Global Health (NVGH)
Country United States 
Sector Private 
PI Contribution Translational links to industry which are critical for future developmental pathways for other areas of activity.
Collaborator Contribution Providing expertise and resource for immune-based studies
Impact Publications, shared expertise
Start Year 2009
 
Description Professor Ben Willcox 
Organisation University of Birmingham
Department Birmingham Cancer Research UK Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Key collaboration for my work. We have started a complimentary collaboration focusing on the recognition of post-transnationally modified antigens.
Collaborator Contribution Joint Studentship
Impact PMID: 19234124, 18836451
Start Year 2007
 
Description Salmonella 
Organisation University of Birmingham
Department College of Life and Environmental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration with CM has led to the isolation of Salmonella-specific antibodies from patients with HIV.
Collaborator Contribution Reagents
Impact In this case I have a collaborative paper which is currently at review with Science we have just submitted a revised manuscript which addresses the reviewers comments.  This work was carried out whilst I was funded by my MRC fellowship. Manuscript details: Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. One sentence summary: High titers of anti-lipopolysaccharide antibody provide a mechanism to account for the long-standing association between HIV infection and susceptibility to fatal nontyphoidal Salmonella bacteremia. Calman A. MacLennan1-4 James J. Gilchrist1,2,5 Melita A. Gordon2,6,7 Adam F. Cunningham1 Mark Cobbold1 Margaret Goodall1 Robert A. Kingsley8 Joep J. G. van Oosterhout2,7 Chisomo L. Msefula2,4,9 Wilson L. Mandala2,9,10 Denisse L. Leyton11 Jennifer L. Marshall1 Esther N. Gondwe1,2,9 Saeeda Bobat1 Constantino López-Macías12 Ian R. Henderson11 Eduard E. Zijlstra7 Gordon Dougan8 Mark T. Drayson1 Ian C. M. MacLennan1 Malcolm E. Molyneux2,7,9 1Medical Research Council Centre for Immune Regulation and Clinical Immunology Service, Institute of Biomedical Research, School of Immunity and Infection, University of Birmingham, UK 2Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi 3Division of Medical Microbiology, University of Liverpool, UK 4Department of Microbiology, College of Medicine, University of Malawi, Malawi 5Oxford University Clinical Academic Graduate School Medical Sciences Division, John Radcliffe Hospital, Oxford, UK 6Gastroenterology Unit, University of Liverpool, UK 7Department of Medicine, College of Medicine, University of Malawi, Malawi 8Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK 9Liverpool School of Tropical Medicine, Pembroke Place, University of Liverpool, UK 10Department of Biochemistry, College of Medicine, University of Malawi, Malawi 11Biosciences, School of Immunity and Infection, University of Birmingham, UK 12Medical Research Unit on Immunochemistry, Specialties Hospital, National Medical Centre "Siglo XXI", Mexican Institute for Social Security, Mexico City, Mexico
Start Year 2009
 
Description Tumour Immunology Partnership 
Organisation University of Virginia (UVa)
Country United States 
Sector Academic/University 
PI Contribution Through my Clinician Scientist Award was able to spend 2 years at the University of Virginia training in Phosphoproteomics and Tumour Immunology.
Collaborator Contribution Providing Reagents, Training and Resources
Impact 18836451 More will follow.
Start Year 2006
 
Title Class i mhc phosphopeptides for cancer immunotherapy and diagnosis 
Description A set of phosphorylated peptides are presented by HLA A*0101, A*0201, A*0301, B*4402, B*2705, B*1402, and B*0702 on the surface of melanoma cells. They have the potential to (a) stimulate an immune response to the cancer, (b) to function as immunotherapeutics in adoptive T-cell therapy or as a vaccine, (c) to facilitate antibody recognition of the tumor boundaries in surgical pathology samples, and (d) act as biomarkers for early detection of the disease. Phosphorylated peptides are also presented for other cancers. 
IP Reference US20130259883 
Protection Patent application published
Year Protection Granted 2010
Licensed Yes
Impact PhosImmune Ltd
 
Title METHODS AND PRODUCTS 
Description The present invention provides improved methods for measuring the ratio of free K immunoglobulin light chain molecules to free ? immunoglobulin light chain molecules in a test sample, using a monoclonal antibody that specifically binds to free K and a monoclonal antibody that specifically binds to free ?. The application also provides specific monoclonal antibodies that can be used in the method of the invention, as well as kits containing said monoclonal antibodies. 
IP Reference WO2010049672 
Protection Patent granted
Year Protection Granted 2010
Licensed No
Impact Possible spin-out in discussion
 
Title TARGET PEPTIDES FOR COLORECTAL CANCER THERAPY AND DIAGNOSTICS 
Description A set of target peptides are presented by HLA A*0201, B*0301, B*0702 and B*2705 on the surface of disease cells. They are envisioned to, among other things, stimulate an immune response to the proliferative disease, e.g., colorectal cancer, to function as immunotherapeutics in adoptive T cell therapy or as a vaccine, facilitate antibody recognition of tumor boundaries in surgical pathology samples, act as biomarkers for early detection and/or diagnosis of the disease, and/or act as targets in the generation antibody-like molecules which recognize the target-peptide/MHC complex. 
IP Reference WO2014039675 
Protection Patent application published
Year Protection Granted 2014
Licensed Yes
Impact A University of Birmingham Spin-Out: PhosImmune
 
Title TARGET PEPTIDES FOR IMMUNOTHERAPY AND DIAGNOSTICS 
Description A set of target peptides are presented by HLA A*0101, A*0201, A*0301, B*4402, B*2705, B*1402, and B*0702 on the surface of disease cells. They are envisioned to among other things (a) stimulate an immune response to the proliferative disease, e.g., cancer, (b) to function as immunotherapeutics in adoptive T cell therapy or as a vaccine, (c) facilitate antibody recognition of tumor boundaries in surgical pathology samples, (d) act as biomarkers for early detection and/or diagnosis of the disease, and (e) act as targets in the generation antibody-like molecules which recognize the target-peptide/MHC complex. 
IP Reference WO2014036562 
Protection Patent application published
Year Protection Granted 2014
Licensed Yes
Impact PhosImmune Ltd
 
Title CMV-IMPACT: Cytomegalovirus Immunoprophylactic Adoptive Cellular Therapy Study 
Description We initiated a Phase II study as part of my Clinician Scientist Fellowship but had to abandon the trial due to EU legislation. CellMedica took the work and have commercilised the technology via a series of clinical trials. These commercial trial were not directly funded by the fellowship but are directly related to and follow on from the work. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This trial has led to the expansion and commercial development of CellMedica including establishments of a manufacturing centre. 
URL http://www.cellmedica.co.uk/technology/our-products/cytovir-immune-reconstitution/cytovir-cmv/
 
Title CMV~ACE/ASPECT Study 
Description The CMV~ACE/ASPECT study is a phase II randomized study to investigate the use of CytovirTM CMV in combination with conventional antiviral drug therapy for the treatment of CMV reactivation episodes in patients following allogeneic hematopoietic stem cell transplant from an unrelated donor. This work, although not part of the MRC Clinician Scientist Fellowship, followed on directly from the work. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Commercial development and progression of CellMedica 
URL http://www.cellmedica.co.uk/clinical-research/cytovir-cmv/ace-aspect/
 
Title Serum Free ? and ? Immunoglobulin Light Chains Assay 
Description Ongoing assay development since 2004 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Publications will follow in 2010. 
 
Company Name SeraScience 
Description SeraScience is an immunodiagnostic company focused on the development of rapid diagnostic and monitoring immunoassays for haematological malignancies, SeraScience was acquired by Abingdon Health Limited in 2014. 
Year Established 2011 
Impact The lead diagnostic SeraLite is currently being used within the NHS for the diagnosis and management of patients with myeloma.
Website http://www.serascience.com/
 
Description Birmingham University Clinical Academic Training 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Aimed at final year medical students and junior doctors aimed at promoting academic medicine regionally

A number of contacts were made.
Year(s) Of Engagement Activity 2009
 
Description British Society for Histocompatibility and Immunogenetics 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Communication of my work to lay people, basic scientists and biomedical scientists.

Potential collaboration with Alex Sette initiated.
Year(s) Of Engagement Activity 2007
 
Description Hospital Grand Rounds (Birmingham) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Presenting Research at University Hospital Birmingham. Presented to around 50 Hospital physicians. Promoted Immunotherapy as an emerging therapeutic.

Other groups within the UHB are planning to use regulatory T cells as immunotherapy.
Year(s) Of Engagement Activity 2008,2009
 
Description UK NCRI Lymphoma Group Biological Studies Dec 2008 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Presentation to haematologists/oncologist dissemination information linked to immunotherapy.

Collaborations initiated.
Year(s) Of Engagement Activity 2008