Day one: 17 November 2004

Present: Professor Norman Nevin (Chair), Professor Terry Hamblin, Professor Jim Neil, Rev Dr Lee Rayfield, Dr Adrian Lepper, Dr Richard Ashcroft, Professor Andrew Lever, Mr Michael Harrison, Professor David Harrison, Dr Michael Waterhouse, Mrs Debbie Beirne, Professor Nick Lemoine, Professor Martin Gore, Dr Caroline Benjamin, Dr Peter Harris, Mrs Fiona Sandford, Dr Mike Mackett (HSE).

Secretariat: Dr Monika Preuss, Dr Cathleen Schulte, Mr Daniel Gooch.

Item 1: Welcome

The Chair welcomed the Committee to its 51st meeting, held at the Department of Health, Elephant and Castle, London, which, due to the need to assess four protocols, would, unusually, be held over two days.

The Chair also informed the Committee that reappointments had been approved by the Health Minister, Lord Warner: Dr Caroline Benjamin will serve for one more year until December 2005; Professor Martin Gore, vice-chair, and Mr Michael Harrison, alternate vice-chair, will serve for another three years until December 2007, as would Mrs Fiona Sandford, Mr Michael Waterhouse and Professor Terry Hamblin. The Chair congratulated members on their reappointments and thanked them for their commitment and the valuable contributions they have made in endeavouring to maintain the highest possible standards of gene therapy research in the UK.

Item 2: Minutes of the 50th meeting of GTAC

The minutes were agreed as an accurate and true record of the 50th meeting.

Item 3: Matters Arising

A number of letters had been sent out (and received) concerning correspondence arising from the last meeting. None of the items gave rise to any discussion.

Item 4: GTAC096: A Phase I Study of Adoptive Transfer of Autologous Tumour Antigen-Specific T Cells with Pre-conditioning Chemotherapy and Intravenous IL2 in Patients with Advanced CEA Positive Tumours

This trial will be conducted with patients who have CEA positive cancers. Carcinoembryonic antigen (CEA) is a protein that is present on the cell surface of a number of tumours including bowel, stomach and pancreatic cancer. Patients will have malignancies that are either metastatic or unsuitable for surgery, and for whom standard curative or palliative measures are not possible. The study aims to modify the T cells of patients so that these cells can mount an immune attack against CEA positive cancer cells. The study product is a retroviral vector which contains two genes which produce an antibody fragment against CEA and the protein of CD3. This is an ex vivo study. It involves the harvest of T cells from patients with CEA positive malignancies, exposure of these T cells to the study vector, followed by the expansion of modified T cells in the laboratory, and, finally, the re-infusion of the modified T cells back to the patient. The proposers joined the committee for a question and answer session. Following this, GTAC decided to approve the study subject to some minor amendments brought up in discussion.

Item 5: GTAC097: NOGA delivery of VEGF for Angina - A Multi-Center, Randomised, Double Blind, Placebo Controlled Study Evaluating the Efficacy of BIOBYPASS® (Adgv VEGF121.10NH) Delivered By NOGA-Guided/MyoSTAR Catheter In "No Option" Patients with Class II-IV Stable Angina

The trial is aimed at patients with class II-IV angina who, after optimal medical treatments, show no improvement and who are not amenable to established re-vascularisation procedures or bypass grafting. The trial proposes to deliver an adenoviral vector expressing vascular endothelial growth factor (VEGF), which stimulates new blood vessel growth, via a heart catheter directly to the heart muscle. It is hoped that new blood vessel growth will improve oxygen delivery to the heart. After some discussion with the proposers, GTAC decided to approve the protocol, subject to revisions to the protocol to reflect the issues discussed.

Item 6: Lentiviral vectors for use in gene therapy (update)

This item included the meeting note following the meetings of the GTAC subgroup on this issue, and correspondence arising from these meetings. GTAC's open letter went out on Friday, 5 November 2004, and a tabled paper contained comments from third parties in response to the letter was provided. The Chairman thanked the members who had helped with this issue for their time and expertise.

Item 7: GTAC 098: A pilot study of lentivirus transduced acute myeloid leukaemia (AML) blasts expressing B7.1 (CD80) and IL-2, for induction of graft versus leukaemia (GVL) effect in poor prognosis, relapsed AML.

This trial is aimed at patients with poor prognosis, relapsed acute myeloid leukaemia (AML). The only long-term cure is provided by a bone marrow transplant from a compatible donor in which the therapeutic effect is mainly due to a graft-versus-leukaemia effect. This is when the transplanted donor cells launch an immune attack against the patient's leukaemic cells and destroy them. The aim of this protocol is to exploit this graft-versus-leukaemia effect. The investigators propose to achieve this by transfecting the patient's AML cells ex vivo with a lentiviral vector that carries the genes for interleukin-2 and a cell surface molecule, CD80. The cells will then be lethally irradiated and returned to the patient. After some discussion with the proposers, GTAC decided to approve the trial subject to revision of the points made in the discussion.

Item 8: Application for enrolment of patients with immunodeficiencies

Three application had been received for patient enrolment into the phase I gene therapy protocols for immunodeficiencies. Enrolment into these studies is subject to case-by-case assessment by GTAC and CSM. After some discussion with the proposers, GTAC decided to approve enrolment of two of the three patients.

Item 9: GTAC 055: Gene directed enzyme prodrug therapy for the treatment of prostate cancer (Phase I intratumoral): Application of substantial amendment

GTAC was asked to consider an amendment to administer second rounds of treatment to (responding) patients enrolled into the therapeutic arm of the trial. The protocol utilises Gene Directed Enzyme Prodrug Therapy (GDEPT) for prostate cancer. Solid tumours are injected with the study product, CTL102, which contains the gene of a pro-drug-converting enzyme called nitroreductase (NTR). Following delivery of CLT102, patients are dosed with the pro-drug (CB1954). Those tumour cells which have taken up CLT102 and produce the enzyme NTR, convert the pro-drug to a toxic form, leading to the death of the cancerous cells. After some discussion, GTAC approved the amendment.

Day two: 18 November 2004

Present: Professor Norman Nevin (Chair), Professor Terry Hamblin, Professor Jim Neil, Rev Dr Lee Rayfield, Dr Adrian Lepper, Mr Michael Harrison, Dr Michael Waterhouse, Mrs Debbie Beirne, Professor Martin Gore, Dr Caroline Benjamin, Mrs Fiona Sandford, Dr Mike Mackett (HSE)

Secretariat: Dr Monika Preuss, Dr Cathleen Schulte, Mr Daniel Gooch

Item 1: GTAC099: A Phase 2 Randomised Double-Blind Placebo-Controlled Parallel-Group Multicentre Dose- Selection Study of Ad2/Hypoxia Inducible Factor HIF-1 alpha/VP16 in Patients with Intermittent Claudication,

This is a trial aimed at patients with peripheral arterial disease (PAD). Patients with PAD in the leg frequently suffer from claudication. This trial will enrol patients with severe intermittent claudication, which is the stage of PAD in which a patient's walking ability is severely limited, causing pain in the legs upon exercise. The study proposes to administer hypoxia induced factor 1a (HIF-1a), a transcription factor that is upregulated in hypoxia. It will then activate VEGF transcription, which in turn will promote new blood vessel growth. The protocol is double-blinded and enrolment is randomised. The treatment will be administered as a single dose into the muscle of both legs with 20 injections in each limb. After a presentation by the proposers and a question and answer session, GTAC decided to approve this trial, subject to the points discussed being addressed.

Item 2: Chairman's Actions

Since the last GTAC meeting, eight Chairman's Actions had been taken, none of which gave rise to any discussion.

Item 3: SAE update

Since GTAC's 50th meeting, the Secretariat had received a number of new SAEs. The clinical details has been summarised in the papers. All SAEs were considered unlikely to be related to the study product, and did not raise any concerns.

Item 4: Genetics White Paper update

Following DH's expression of interest exercise for gene therapy vector production the Department had received 20 bids for such funding. The Secretariat provided the programme for an information-gathering workshop being organised by DH on 15 December 2004 to explore the different possibilities on how this could be taken forward. Dr Peter Harris had kindly accepted DH's invitation to chair the meeting.

Item 5: Any other business

There were no items.

Next meeting: Wednesday, 16 February 2005

GTAC Secretariat
January 2005

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