CMV TCR Gene Therapy: A Phase I/II Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy in Allo-HSCT

Lead Research Organisation: University College London
Department Name: Infection

Abstract

Patients with cancers of the blood and bone marrow are often given a form of treatment called a stem cell (or bone marrow) transplant. During the transplant procedure the patient will be given potent chemotherapy and/or radiotherapy to kill off residual cancer cells before the new stem cells are re-infused from the bone marrow donor, often a sibling. In order for the new stem cells to persist in the patient, powerful drugs need to be given to suppress the patient?s own immune system. The period of profound immune suppression can last for up to 6 months post transplant. During this time the reactivation of viruses, such as cytomegalovirus (CMV) is very common. CMV reactivation in immunosuppressed patients can lead to progressive infection and even death. In healthy individuals CMV rarely causes any problems as the T cells of the immune system are able to keep the virus in check. Individuals who have previously been infected with CMV (50% UK adults) have small numbers of T cells in their blood which can recognise and kill CMV-infected cells. Recently, researchers in the UK and Europe have shown that these CMV-specific T cells taken from bone marrow donors can be infused into the transplant patient and control CMV infection in the patient. Typically, a single infusion of the donor?s T cells is effective. This approach avoids the need for repeated anti-viral drugs, which have significant side effects and usually require the patient to be re-admitted to hospital for prolonged periods.
However, many patients have transplant donors who have not been previously infected with CMV. These donors will not have any pre-made immune T cells which can recognise CMV. We propose to take the T cells of CMV negative donors and genetically modify them so that they are able to recognise and kill CMV-infected cells. This will be done by growing the donor T cells in the laboratory in the presence of a specially modified virus called a retroviral vector. This procedure will transfer a gene to the T cells, which allows them to recognize protein fragments (peptides) of the CMV virus called CMV pp65. The gene transferred to the T cells enables them to make a new T cell receptor (CMV TCR), which specifically recognises the CMV pp65 peptide. The CMV TCR gene-modified T cells will be infused into the patient if they reactivate CMV as part of this Phase I/II clinical trial.

Technical Summary

The proposed Phase I/II proof of concept pilot study will test the feasibility of generating donor-derived CMV-specific T cells via the ex vivo introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector. It will also determine the safety, toxicity and efficacy of CMV TCR-transduced T cells used for the pre-emptive treatment of CMV reactivation following HLA-matched sibling allogeneic haematopoietic stem cell transplantation (Allo-HSCT).
Reactivation of the latent human herpes virus, Cytomegalovirus (CMV) post allogeneic haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious side effects, such as myelosuppression (Ganciclovir) or nephrotoxicity (Foscarnet). Cellular immunotherapy for CMV has been tested in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated from the peripheral blood of CMV seropositive donors and re-infused into recipients following CMV reactivation resulting in sustained anti-viral responses. Transplant recipients with CMV seronegative donors cannot benefit from currently available cellular immunotherapy approaches due to the lack of CMV-specific memory T cells in these donors. At present, there is no reliable strategy to isolate virus specific T cells from uninfected na?ve individuals, as the precursor frequency is low or absent and the in vitro priming of T-cell responses is inefficient. T-cell receptor (TCR) gene transfer offers a strategy to produce antigen-specific T cells independent of precursor frequency and without the need for T-cell priming. We propose that CMV TCR-transduced T cells, generated from CMV-seronegative donors, can generate protective CMV immunity in post-transplant patients.

Publications

10 25 50
 
Description Influence on UK policy
Geographic Reach UK 
Policy Influence Type Participation in a national consultation
Impact DOH/GTAC/MHRA workshop to discuss impact of genetics white paper and discuss future cell and gene therapy strategy. Minutes taken for the purposes of providing advice to Ministers.
 
Description MRC DPFS
Amount £245,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2010 
End 10/2012
 
Description MRC Training Fellowship
Amount £253,094 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Title MHRA-approved ATMP Manufacturing process 
Description Our collaborators at GOSH have (with our help and in order to deliver the MRC-funded funded c;inical trial) secured and MHRA manufacturing license to produce clinicala grade genetically modified T cells for use in clinical trials. This has required the development of a specific quality system, referurbishment of new labs and training of staff, including those from our research group. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact This infrastructure development was a pre-requisite to carry out the MRC-funded clinical trial. The facility is also available to others on a collaborative basis. 
 
Title RT-PCR for the detection of genetically modified T cells 
Description An assay has been developed to determine the endpoint 'persistence of TCR-transduced T cells' where FACs analysis of peripheral is insufficiently sensitive. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact required to interpret clinical trial data 
 
Description Birmingham Early Phase Clinical Haematology Trials Unit 
Organisation University Hospitals Birmingham NHS Foundation Trust
Department Haematology
Country United Kingdom 
Sector Hospitals 
PI Contribution We have worked closely with Birmingham to set up multi-centre Phase I clinical trials of T cell immunotherapy in Haematology patients.
Collaborator Contribution Early Phase Clinical trial support and set-up.
Impact Clinical study funded by current MRC grant is in set-up. GTAC approval granted. MHRA submission pending. Previous LLR-funded trial with Birmingham has completed.
Start Year 2006
 
Description Centre for Cell, Gene and Tissue Therapeutics, Royal Free London Hospital NHS Trust 
Organisation Royal Free London NHS Foundation Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution My team and I have negotiated a move from GOSH to the CCGTT for the manufacture of GMP-modified T cells for this trial. Intellectual input and technical support.
Collaborator Contribution GMP manufacture of therapeutic T cells has been optimised and moved to the CCGTT. Staff have been trained in using different equipment, including the Prodigy system. Amendments to the manufacturing process have been validated and submitted to MHRA and NRES for approval which have been received. One member of my research team is now acting QC manager for the unit to support its exapnsion of activity.
Impact 1. Staff trained in using Prodigy closed system for gene modification of immune cells 2. Improved manufacturing process for gene modified T cells submitted as a substantial amendment and approved by MHRA and NRES
Start Year 2016
 
Description Great Ormond Street Hospital Gene Therapy Laboratory 
Organisation Great Ormond Street Hospital (GOSH)
Department Department of Immunology
Country United Kingdom 
Sector Hospitals 
PI Contribution We have generated protocols for the clincal scale production of genetically modified T cells for clinical use. We have prepared regualtory paperwork. We have provided research staff to work in the GOSH Gene Therapy Lab
Collaborator Contribution We have collaborated to establish an MHRA-approved ATMP manufacturing facility to generate genetically modified T cells for clinical trials
Impact Generation of Clinical grade CMV TCR gene-modified T cells for use in the clinical trial funded by the current MRC grant.
Start Year 2008
 
Title GMP grade retroviral vector 
Description GMP grade retroviral vector encoding the TCR alpha and beta chain genes for a human CMV-specific T cell receptor (TCR) has been generated and tested in clinical GMP scale ups in preparation for the early phase clinical trial. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Granted full GTAC approval July 2010, which allows us to proceed to first in man clinical trial. 
 
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 
 
Description DOH/GTAC schools visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Explaining genetically modified T cells for immune therapies and answering questions/concerns about gene therapy

Nuffield Foundation Summer student hosted in my lab
Year(s) Of Engagement Activity 2008
 
Description Department of Health Gene Therapy Workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact Attended by policy makers and recorded for Secretary of State for Health and Health Minister. Aimed to reinforce requiremnet for investment in gene therapy in the UK.

Have been invited to discussion meetings with MHRA subsequently.
Year(s) Of Engagement Activity 2008
 
Description Graveney Project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I have started a project with 20 year 11 students, to perform experiments on gene-engineering in their classroom. I attend every fortnight. We have secured funding to pay for teacher time and equipment/consumables. Students are designing primers, perfomring PCR etc.
Year(s) Of Engagement Activity 2016,2017
 
Description LRF Annual Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Fundraisers, patients and public attending open day to hear about research in department. Lay talks given to explain basic science research and experimental clinical trials. Also included description of MRC funded research.

Letters from patients and public.
Year(s) Of Engagement Activity 2008
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact 500 pupils attended a special assembly led by myself on science, medicine and experimental medicine. MAny questions and much interaction.

Repeat visit requested and more detailed talks to senior classes requested.
Year(s) Of Engagement Activity 2011