Commission of Somatic Gene Therapy decides Continuation of Some of the Gene Therapy Studies with Retroviral Vectors

Certain clinical gene therapy trials using retroviral vectors will be recommended for initiation or continuation in Germany. This is the result of a meeting of the Commission of Somatic Gene Therapy (Kommission Somatische Gentherapie (KSG)) of the Scientific Council of the German Medical Association (Bundesärztekammer) in agreement with the Paul-Ehrlich-Institut on Tuesday, 4th February 2003. Two cases of a leukaemia-like disease recently occurred in France in a gene therapy study for the treatment of the congenital immunodeficiency disorder SCID-X1 ("Severe Combined Immunodeficiency Disease"). Following this, other gene therapy studies using retroviral vectors were also put on hold as a precautionary measure to allow the reassessment of the benefit/risk ratio.

Specifically, it has been decided to recommend the initiation of an AIDS gene therapy trial under observation of strict restrictions. Two other studies for the treatment of the graft-versus-host disease (GvHD) received a positive recommendation as early as January 2003, following the submission of protocol changes including an explicit notice on the cases of leukaemia in the French gene therapy study in the patient information leaflet (see below). A recommendation of a gene therapy trial on rheumatoid arthritis was postponed due to still pending improvements in the protocol that have become necessary. There have been, however, no principle objections to a local gene therapy of rheumatoid arthritis using retrovirally modified synovial cells. In contrast, the existing recommendation to put on hold the clinical trial on Chronic Granulomatous Disease (CGD) will be maintained until the risk of leukaemia after treatment with retrovirally modified blood stem cells can be assessed more accurately. Here, additional scientific knowledge is expected in the next few months.

Prof. Klaus Cichutek, Vice President of the Paul-Ehrlich-Institut and Chairman of the Commission of Somatic Gene Therapy, summarised the decision as follows: "The recommendations of the Commission of Somatic Gene Therapy and the Paul-Ehrlich-Institut take into account current knowledge about the leukaemia risks associated with the use of retroviral vectors. They also highlight that retroviral vectors can still be used in gene therapy in the future." A risk/benefit analysis based on current findings as well as the advice provided by the Commission of Somatic Gene Therapy and the competent authorities to the applicants would guarantee the maximum possible safety and on time consulting about possible risks. Based on this framework, the development of novel therapies would be gradually acceptable in future, too, even if an increased risk occurred.

Background Information

The background for the reassessment of the German clinical trials as mentioned above was the recent occurrence of two leukaemia-like lymphoproliferative diseases in children whose congenital immunodeficiency disease SCID-X1 was treated with retrovirally modified bone marrow stem cells during a French gene therapy study (principal investigator: Dr. Alain Fischer) approximately three years ago. Complete verbal information from Alain Fischer and his scientific collaborators on the recent findings concerning the mechanisms underlying the leukaemias was available to the German Medical Association and the Paul-Ehrlich-Institut at the time of the decision. There is a well-founded reason that the insertion of the vector (insertion of the retroviral vector into the LMO2-gene in the genome of the modified blood stem cells) in the context of the approach to SCID-X1 gene therapy caused the leukaemia-like disease of the white blood cells in both children. On a world-wide basis, up to now, only the two leukaemias observed during the SCID-X1 gene therapy study have been suspected to be related to the use of certain vectors. However, it cannot currently be ruled out that other therapies using retrovirally modified blood stem cells may also carry a risk of leukaemia development.

The experts of the Commission of Somatic Gene Therapy and the Paul-Ehrlich-Institut agreed that according to the state of the art, the assessment of the risk of leukaemia following treatment with live retrovirally modified cells seems to depend on the following factors:

• the type of the retrovirally modified cell,
• the amount of cell proliferation to be expected in the body (in-vivo expansion) and the concurrent natural mutation rate,
• the number of retrovirally modified cells to be transferred,
• the influence of the therapeutic gene on cell proliferation and/or differentiation, and
• the age of the patient to be treated.
• In addition, the severity of the disease was taken into account in the risk/benefit analysis.

The experts see a reduced risk for the treatment with retrovirally modified lymphocytes or other somatic cells compared to blood stem cells. In addition, the therapeutic genes transferred during CGD, HIV and GvHD gene therapy are not suspected to contribute to cell proliferation and thus tumour induction. The risk is therefore increased in the CGD study, since this therapy uses modified stem cells the cell proliferation of which is planned to be stimulated by chemotherapy as a preparation of the gene therapy. Initiation of the HIV gene therapy study can be recommended since in this study, lymphocytes are modified and the therapeutic gene is not suspected to induce increased cell proliferation. The recommendation to start the HIV gene therapy study is made on condition that the patients included in the study are restricted to those AIDS infected individuals who are resistant to approved anti-retroviral chemotherapeutics. Similar reasons apply to the recommendation to resume the GvHD studies in which no genes which stimulate cell proliferation are used either. In these studies, too, patients with life-threatening conditions are treated.

The competent ethics committees which have been formed in conformity with the laws of the Länder (German states) are now entitled to decide on the studies for which initiation or continuation has been recommended. In the event of a positive vote from these ethics committees, the required changes in the protocols must be submitted to the Paul-Ehrlich-Institut. The institute will then recommend the start or continuation of the study previously put on hold to the competent authorities of the Land.

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