Hold of Clinical Gene Transfer Studies in Germany (Following the Diagnosis of a Leukaemia in a Gene Therapy Patient in France) Serves the Purpose of Ethical Re-Consideration and Adaptation of the Patients´ Information Leaflets

The decision by the Paul-Ehrlich-Institut and the Commission for Somatic Gene Therapy (Kommission Somatische Gentherapie (KSG)) of the Scientific Council of the German Medical Association to recommend putting on hold all clinical studies involving the use of live, retrovirally modified cells was preceded by a discussion of the causes of a leukaemia diagnosed in a patient treated by gene therapy during a clinical study in France. Amendments to be submitted will serve to renew the benefit / risk analysis, to make reference of the case of leukaemia in the patient's information leaflet, and to possibly reconsider the inclusion and exclusion criteria. This will be followed by a decision on the studies concerned by the KSG in consultation with the Paul-Ehrlich-Institut following the next KSG meeting at the end of November 2002. In order to foster international collaboration, the KSG and the Paul-Ehrlich-Institut have informed competent authorities, professional bodies and ethics committees in Europe and the United States at an early time point about the decision made in Germany.

Before the decision was made (following the international expert meeting at the Paul-Ehrlich-Institut in Langen, Germany, on Tuesday, 17th September 2002) to recommend the suspension of all clinical studies in Germany using live, retrovirally modified cells, available information concerning the possible mechanisms underlying the induction of leukaemia in one of the patients enrolled in a clinical gene transfer study in France was already taken into account. The KSG and the Paul-Ehrlich-Institut had obtained detailed information on the circumstances which led to the hold of the clinical study in France from Dr. Alain Fischer and from the French Medicines Agency AFSSAPS.

On request of the French principal investigator, this information was disclosed only to concerned authorities, ethics committees and principal investigators because at that time not all parents of the children enrolled in the clinical study had been informed about the leukemia diagnosis. On 3rd October 2002, the case of leukaemia was published in France. Results of the studies performed on the leukaemic cells obtained from the patient were presented to the public during the ESGT ("European Society of Gene Therapy") Conference on 16th October 2002.

In Germany, clinical studies were put on hold in order to protect enrolled patients from possible risks and, above all, to enable them to make a decision on the basis of complete information. The clinical hold shall allow for sending in amendments of the concerned study protocols. It was recommended to the principal investigators to mention the case of leukaemia following gene therapy in the patient's informed consent form, to reconsider the inclusion and exclusion criteria and, if necessary, to specify them, and to re-evaluate the ethical acceptability of the individual studies. The amendments submitted will be evaluated by the KSG and the Paul-Ehrlich-Institut in late November and form the basis for the decision on continuation or discontinuation of the clinical studies on a case-by-case basis.

The data published by Li et al. (Science 296, 497 (2002) - the item requires a AAAS Member subscription to SCIENCE Online) on the occurence of leukaemia in mice and the data available on the leukaemia diagnosed in one of the fourteen SCID-X1 ("Severe Combined Immunodeficiency Type X1") patients treated show similarities. In both cases, a leukaemia was observed after retroviral gene transfer into blood stem cells. It cannot be ruled out that, in conjunction with other factors, integration of a retroviral vector into the genome of a modified cell resulting in the activation of a proto-oncogen (insertional mutagenesis with the result of oncogenesis) can be the cause of leukaemia. Possible other factors include interference with cellular signal transduction pathways and thus, growth control mechanisms of the target cells by the transferred gene, the nature of the target cell and its expansion in vivo, familial predisposition for cancer, infections during the course of the treatment and the patient's age.

In the French SCID-X1 patient, a vector integration was found in the transformed gamma delta T cells near the lmo-2-gene, which, as a proto-oncogene, controls cell differentiation. The integration may have led to the strong over-expression of the Imo-2-gene found in the tumour cells. The product of the transferred gamma-c-chain gene is part of cytokine receptors which can influence cell growth. In addition, there are speculations regarding further, until now unidentified mutagenic events favoured by the extensive proliferation of the modified cells in vivo, familial factors or a chicken pox infection. The possible contribution of the above-described factors to leukaemia development has as yet been unproven. The patient's leukaemia is currently treated using conventional methods and there are prospects for successful treatment.

After weighing the risk of development of leukaemia following retroviral gene transfer against the benefit of individual gene therapy studies for the patients, it possible that some clinical studies may be continued. This will be decided by the KSG and the Paul-Ehrlich-Institut case-by-case.

Vice President of the Paul-Ehrlich-Institut
Chairman of the Commission of Somatic Gene Therapy of the Scientific Council of the German Medical Association

Background Information:

In Germany, the following clinical studies using live, retrovirally modified cells have been registered since 1994 (application at the KSG and/or submission in compliance with Article 40 of the German Drug Law (Arzneimittelgesetz (AMG)) at the Paul-Ehrlich-Institut or the "Bundesinstitut für Arzneimittel und Medizinprodukte" (BfArM) (Federal Agency for Medicinal Products and Medical Devices):

1. Gene Therapy of a monogenic hereditary disorder:
   For the treatment of the life-threatening hereditary disorder(CGD) "Chronic Granulomatous Disease"), autologous blood stem cells are transplanted, the gene defect of which was corrected by retroviral transfer of a functionally intact gene. This serves to alleviate, or even cure, the congenital immune deficiency.
   Status: 1 registered study; on hold.
2. GvHD treatment by 'suicide gene' transfer and administration of Ganciclovir:
   Suppression of graft-versus-host disease during the treatment of leukaemia by transplantation of foreign (allogeneic) blood stem cells and lymphocytes. The transfer of allogeneic donor lymphocytes is a conventional therapy which, after prior chemotherapy and stem cell transplantation, leads to a suppression of leukaemia (donor-versus-leukaemia effect). However, a strong immunological reaction (graft-versus-host disease; GvHD) caused by the transplanted lymphocytes can occur and may cause possibly life-threatening complications. If allogeneic donor lymphocytes are used into which a drug-inducible cell-killing gene ("suicide gene"; thymidin kinase gene of the Herpes simplex virus) was transferred by a retroviral vector, these cells can be killed in vivo by administration of the specific drug Ganciclovir in the event of a severe GvHD. This treatment therefore helps to avoid life-threatening complications.
   Status: 4 registered studies; on hold.

3. HIV gene therapy:
   The transfer of lymphocytes which bear an HIV inhibiting gene serves to suppress HIV replication in the body.

   Status: 1 registered study, not started.

4. Use of an indicator gene to analyse haematopoetic reconstitution:
   Gene-marked cells are transferred as part of a conventional leukaemia treatment by blood stem cell transplantation. During haematopoetic reconstitution, the amount and type of emerging blood cells are analysed.

   Status: 3 registered studies; on hold.

5. Local gene therapy of rheumatoid arthritis:
   (Synovial) cells are removed from the joints affected by arthritis. After transfer of a gene (IRAP, "interleukin receptor antagonist"), the product of which can block factors contributing to the inflammation of the joint (cytokines), the modified cells are re-transferred to the joint.
   Status: 1 registered study; on hold.
6. Transfer of drug-resistance-gene-modified blood stem cells during high-dose chemotherapy of malignant tumours:
   The efficiency of cancer therapy is intended to be improved by high-dose chemotherapy. Since blood cells may be damaged by chemotherapy, these cells are intended to be protected by a gene which confers resistance against several drugs (mdr = "multiple drug resistance gene"). The mdr gene is transferred to the blood stem cells before stem cell transplantation.
   Status: 2 registered studies; completed. 1 registered study, negative appraisal, therefore not started.
7. Brain tumour treatment by injection of mouse cells producing a suicide vector, followed by administration of Gancilovir:
   In patients with progressive disease, live murine vector packaging cells are transferred during brain surgery. The cells release retroviral vectors transferred to residual tumour cells. The vectors transfer a suicide gene to the tumour cells which makes the tumour cells susceptible for the cell-damaging effect of Ganciclovir. After Ganciclovir administration, these tumour cells and the vector packaging cells should be killed in the body.
   Status: 4 registered studies; completed.

If you need additional information, please contact Susanne.Stoecker@pei.de.