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Seeking the Cause of Induced Leukemias in X-SCID Trial

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Science  24 Jan 2003:
Vol. 299, Issue 5606, pp. 495
DOI: 10.1126/science.299.5606.495

Details of a second case of cancer in a gene-therapy trial in France, revealed last week, raise the odds that both were therapy induced. In both cases, a retrovirus engineered to shuttle corrective genes into cells inserted itself in or near a cancer-causing gene, apparently triggering uncontrolled cell growth. The risks seem “surprisingly high,” says pediatrician Alain Fischer, who with Marina Cavazzana-Calvo led the trial at the Necker Hospital for Sick Children in Paris.

The French team has restored the immune systems of nine of 11 boys with X-linked severe combined immunodeficiency disease (X-SCID), making this the first clear success in gene therapy. But the appearance of two cancers, one in September and a second in December, is a major setback for the field (Science, 17 January, p. 320).

Last week, the U.S. Food and Drug Administration (FDA), which was already reviewing three other SCID trials, put a hold on 27 additional U.S. trials using retroviruses to insert genes into blood stem cells. The National Institutes of Health's (NIH's) Recombinant DNA Advisory Committee (RAC), meanwhile, postponed a planned emergency meeting to allow investigators to gather more data.

The RAC released information from Fischer's team last week, revealing that in both cases of leukemia, the problem arose from an overproduction of immune cells in the blood. The first case involved the replication of a single γδ T cell, and the second involved an excess of three types of an αβ T cell. The problem in the second patient may have occurred in a young, undifferentiated cell that gave rise to three αβ T cell subclones, says molecular biologist Christof von Kalle of Cincinnati Children's Hospital Medical Center in Ohio, who is collaborating with the French team. Although experts had thought that other factors might have contributed to the first child's leukemia— including a chickenpox infection and a family history of cancer—the second child apparently did not share the same risk factors.

Searching for answers.

Christof von Kalle (with research assistant Barb Jensen) probes the molecular events that led to leukemia in two patients.


Von Kalle's lab has found that, in both patients, the vector inserted itself near the same gene, LMO2, which has been linked to leukemia. “It is a surprise. There's no good explanation at the moment,” says gene-therapy expert Inder Verma of the Salk Institute for Biological Studies in La Jolla, California. The French team's hypothesis is that the gene inserted to correct the X-SCID problem (common γ chain, or γc) may be playing a crucial role. This vector contains a sequence that promotes γc, which in turn boosts the production of T cells. In a cell in which the vector has landed near and also activated the LMO2 gene, LMO2 may be cooperating with γc, giving cell growth an extra kick. If so, even if just one cell in 100,000 carried the insertion in or near the LMO2 gene, it could multiply quickly enough to dominate the T cell population, notes von Kalle.

This gene insertion may seem “frightening” because it can lead to cancer, says Theodore Friedmann, a gene-therapy researcher at the University of California, San Diego, and chair of the RAC group. But there is also reason for optimism: The technique is producing therapeutic results, and the adverse effects might be “specific to the X-SCID trials,” von Kalle says. Other SCID trials that don't involve the same vector sequences might be safe, he and others suggest. Moreover, it may be possible to modify X-SCID gene therapy to reduce risks. For example, researchers could use a regulated promoter sequence for γc and target fewer cells. In addition, trials that begin therapy when children are older may lower the risk for harmful alterations in immature T cells.

Researchers are awaiting more data before they attempt to reassess the risks. RAC aims to have more details in hand in early February, when it will hold an open meeting, says Stephen Rose of NIH's Office of Biotechnology Activities. By then, von Kalle expects to have data on precisely where the therapeutic gene inserted itself and whether it activated LMO2. An FDA advisory committee will take up the case in late February, and the American Society of Gene Therapy, which issued a press release supporting the suspension of trials, also expects to undertake a review.

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