ASGT Press Release

American Society of Gene Therapy Responds to a Second Case of Leukemia Seen in a Clinical Trial of Gene Therapy for Immune Deficiency

(MILWAUKEE) A second serious adverse event, similar to the one reported in September 2002, has been observed in a clinical trial of gene therapy for the X-linked form of severe combined immune deficiency disease (XSCID) being performed by Alain Fischer, MD, Marina Cavazzanna-Calvo, MD and colleagues at the Hôpital Necker Enfants Malade, Paris, France.

In response, the Board of Directors of the American Society of Gene Therapy (ASGT) supports the Food and Drug Administration's (FDA's) decision to put protocols of this type on clinical hold until further assessment of risk to patients can be assessed and has initiated a comprehensive review to understand the cause of the leukemia developed in two of the 10 infants treated for XSCID by gene therapy. The ASGT also encourages heightened caution in the further enrollment of new subjects in other clinical trials involving retrovirus-mediated gene transfer to hematopoietic cells and urges all investigators conducting retroviral mediated gene therapy to review available data and reassess the risks and benefits of their clinical trial. If warranted, informed consent documents should be revised after consultation with the appropriate regulatory bodies.

ASGT will establish an ad hoc committee of scientists to collect and analyze the relevant data that exists from among many individual studies performed world-wide, including experimental research studies in animals and the relevant clinical trials. The accumulated data and analyses will be presented in a scientific symposium at the 6^th annual meeting of the ASGT in Washington DC, June 2003. Understanding the mechanisms that underlie the development of leukemia may lead to improved methods of gene therapy for this inherited immune deficiency disease that can minimize the risks but preserve the benefits that have been seen in this trial. As with all clinical research, patient safety is of paramount importance and all possible efforts must be made to minimize risks.

The results of the deliberations of the ad hoc committee will also be posted publicly at the society's web-site (www.asgt.org) and would be available to regulatory and advisory agencies to assist in their assessments of the risks and benefits of this new form of therapy. ASGT continues to work closely with the FDA and Office of Biotechnology Activities/National Institutes of Health to examine the scientific, medical and ethical issues involved with gene therapy studies.

The clinical trial of gene therapy for X-linked severe combined immune deficiency (XSCID) performed by the French investigators still has seven of 10 subjects in good health with their immune systems restored by the gene treatment (one child was too ill at the time of the procedure to benefit). These findings highlight the potential of gene therapy to correct this otherwise fatal immune disorder without complications such as graft rejection that may be seen when hematopoietic stem cells from another donor are used in a "standard" bone marrow transplant approach.

A key scientific question to be explored is why this problem has only been seen so far in this study of infants treated for XSCID, but not in any of the other clinical trials using retroviral vectors targeted to hematopoietic stem cells (or any other trial of gene therapy). There may be unique unrecognized features of the specific gene (called GammaC, which encodes a T cell growth factor receptor), the specific disease (XSCID), the subjects' age (infancy), or some aspect of the gene transfer methodology that increased the risks of triggering leukemia.

SCID, often referred to as "bubble baby disease," is a genetic disease with severe defects in T cell and B cell immunity. If untreated, SCID is usually fatal in the first years of life, due to severe and recurrent infections. The treatment of choice for SCID is a bone marrow transplant from a healthy brother or sister who is a perfect "tissue-type" match. Unfortunately, most patients with SCID lack such a matched donor and must turn to other treatment options. Use of bone marrow from a parent or an unrelated donor is successful in only 60-70% of infants, with a significant number of subjects gaining only partial immune restoration. Moreover, there is the risk of development of lymphoma in bone marrow transplant patients who receive cells from a donor who has had infectious mononucleosis. Thus, investigations of new treatments such as gene therapy are vital to improve the survival rate of these patients.

To improve the outlook for infants who lack a matched sibling donor, gene therapy has been under investigation in the United States and abroad. The gene therapy procedure involves insertion of the corrective gene into the patient's own hematopoietic stem cells from bone marrow followed by transplantation, thus avoiding transplant rejection. The corrected stem cells produce immune competent T and B cells thereby achieving effective immunity. Notably, the gene transfer approach of the Paris clinical trial led to life-saving immune recovery in 9/10 (90%) of the treated infants, who were able to go home.

However, one of the subjects of this gene therapy trial was observed in September 2002 to have developed T cell leukemia, about three years after the gene therapy procedure. Leukemia is a form of cancer in blood-forming cells. In December 2002, a second subject was diagnosed with a similar leukemia-like illness. Both subjects have been treated with conventional chemotherapy to attempt to eliminate the leukemia.

Dr. Fischer and a number of other independent experts are working to try to characterize the events that led to leukemia in these patients and whether there existed any predispositions to develop leukemia that was enhanced by the gene therapy. It will be necessary to weigh the frequency of this type of complication from gene therapy against the risks and benefits of other methods of treatment and determine which will be best for patients. It is widely believed that development of cancer in humans depends on a complex series of genetic and biological events that are not completely understood, and therefore, it is not possible, at the current time, to fully understand the role of the gene transfer process in the development of the leukemias that have arisen in the two patients. Nevertheless, based on extensive studies of animal models of cancer, and particularly the association between the disregulated expression of a number of specific genes and the development of different human cancers, it is highly likely that the insertion of the retroviral vectors into the specific regions of chromosomal DNAs observed in those two patients contributed significantly to the development of their cancers

A retroviral vector was used to carry the gene into the patients' hematopoietic stem cells from their bone marrow. Retroviral vectors insert into the chromosomes of the cells they enter, which allows the gene they carry to be stably copied and passed on to all of the cells that are produced from the hematopoietic stem cell. Retroviruses can contribute to cancerous changes in a cell if they insert into the cell's chromosomes near a cellular gene that regulates growth. The complication of cancer or leukemia was previously thought to be a possible but very unlikely risk with the type of vector used in this study, since these vectors cannot reproduce themselves and so cannot repeatedly insert into the cell's chromosomes, the process that is most likely to lead to a malignant change. This risk of cancer as an adverse side effect of gene therapy is stated explicitly in the informed consent statements that describe the risks and potential benefits to patients and their families. No evidence of leukemia or other forms of cancer were seen in the extensive pre-clinical studies performed before the trial was begun.

The American Society of Gene Therapy is a professional, non-profit medical and scientific organization dedicated to the understanding of gene therapy and to promoting professional and public education in this field.

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