Clinical Studies with Retroviral Gene Transfer on Hold

The Bundesärztekammer (German Medical Association) and the Paul-Ehrlich-Institut (PEI) maintain and expand their recommendation from June 2002 to put clinical studies involving the use of retroviral gene transfer on hold. No further patients shall be treated with retrovirally modified cells until further decisions have been made. This is the result of a discussion during an international expert meeting held at the Paul-Ehrlich-Institut in Langen on Tuesday, 17th September 2002, hosted by both the 'Kommission Somatische Gentherapie' (KSG; 'Commission for Somatic Gene Therapy' of the Scientific Council of the German Medical Association) and the PEI.

The goal of the expert meeting was to review possible risks of certain gene therapy methods and to discuss the consequences for clinical gene therapy trials in Germany. The discussions focused on cell modifications by means of retroviral vectors and the use of the so-called Δlngfr gene ("delta low affinity nerve growth factor receptor") in lymphocytes and blood stem cells. The Δlngfr gene is being used for enriching blood cells successfully modified with a therapeutic gene, before they are transferred to the patient.

The discussion was started on the basis of a report by Prof. Baum's group at the Medizinische Hochschule Hannover (University for Medicine). According to this report, mice that had received Δlngfr-modified blood cells had developed a disease comparable with Acute Myeloid Leukaemia (AML).

Representatives of competent authorities, medical experts and the principal clinical investigators working with such gene vectors in Germany came to attend the meeting organised by the KSG and the PEI. The experts concluded that the data obtained from animal experiments gave only minor evidence for the Δlngfr gene as a factor contributing to the development of murine leukaemia. However, they did rate the data as a clear example for the occurrence of cancer due to the retroviral insertion of genes in the genome of somatic cells. Therefore, the experts also discussed the international state of the art regarding cancer risks after retroviral gene transfer in humans at the meeting.

"We regard the risk of leukaemia following retroviral gene transfer as low. However, based on new findings, it is clearly existent. For the patients concerned, this risk must again be weighed against the expected benefit of the specific gene therapy to be applied," explained Prof. Dr. Klaus Cichutek, Vice-President of the Paul-Ehrlich-Institut and chairman of the 'Commission of Somatic Gene therapy' after the meeting. The KSG and the PEI will make a decision on the possible continuation of the studies amendments with such risk-benefit evaluations have been reviewed (by the KSG and the PEI).

According to Prof. Cichutek, the benefit / risk ratio will have to be reassessed in general, if leukaemia occurred during the use of retroviral vectors in clinical studies. "Due to lack of experience, final assumptions cannot yet be made about the possible risks of new therapy strategies such as gene therapy due to a lack of experience. Therefore, such therapies may only be used in patients with life-threatening conditions, if the benefits clearly outweigh the risks. Once this is guaranteed, however, clinical development must continue in order to find innovative therapeutic strategies", as Mr. Cichutek emphasised.

Background Information:

In Germany, clinical trials have been carried out using retroviral gene transfer mainly for two forms of therapy. These trials have now been suspended:

1. Treatment of the life-threatening monogenous congenital disorder Chronic Granulomatous Disease (CGD). During treatment, the patient's own blood stem cells are transferred back to him after their genetic defect has been corrected by means of retroviral transfer of the functional gene. This treatment is intended to help alleviate or cure the congenital immune deficiency.
2. Suppression of complications caused by rejection of donor lymphocytes in leukaemia therapy. The transfer of donor lymphocytes is a conventional treatment which leads to the suppression of leukaemia (graft versus leukaemia effect) after prior chemotherapy and stem cell transplantation. However, life-threatening complications can occur in the form of an excessive immunological reaction caused by transferred lymphocytes (graft versus host disease (GvHD). If donor lymphocytes are used which carry a pharmaceutically activatable cell-killing (suicide) gene transferred using a retroviral vector, these cells can be killed in the human body by administration of a specific drug, if a severe GvHD occured. Thereby the life-threatening GvHD can be avoided.

Link to a Press Release of the French Agence Francaise de Securité Sanitaire des Produits de Santé, (Afssaps) concerningleucaemia within a clinical trial in gene therapy

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