Data from a new clinical trial using gene therapy to treat X-linked severe combined immunodeficiency (X-SCID), sometimes known as "bubble boy disease," suggest that a new vector used to deliver the IL2RG gene was as effective as previously used vectors, but it may be less likely to cause the leukemia that befell 5 of 20 patients in two earlier trials. (See BioWorld Today, May 1, 2000, Jan. 16, 2003, and Dec. 20, 2007.)

The trial results, which their authors published in the Oct. 9, 2014, issue of the New England Journal of Medicine, are preliminary. The average follow-up for patients in the current trial is 29 months; the leukemia cases in the earlier trials developed after two to five years, with a median of 33 months.

But if one knows where to look, signs of trouble can be seen before outright leukemia develops. No such signs are visible in the nine patients treated with the new viral vector, "giving us some optimism that the vector will prove safer . . . while the efficacy is comparable," co-lead author Sung-Yun Pai, of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, told BioWorld Today.

In the early 2000s, a total of 20 boys who lacked a functional IL2RG gene, which is critical for development of the B and T cells of the adaptive immune system, were treated with gene therapy using a gamma-retroviral vector in two separate, but very similar, trials in Paris and London.

The therapy initially looked like a breakthrough success, reconstituting the immune system in most of the treated patients and literally giving a new chance at life to baby boys who otherwise had little chance of making it to their first birthdays. (See BioWorld Today, May 1, 2000.)

But that triumph was followed by the realization that the vectors used in the study put the treated children at risk of developing leukemia, leading to what Pai called "a dramatic dampening of enthusiasm" for gene therapy in general.

Nevertheless, the fact remained that gene therapy was able to cure children who otherwise have very little chance of survival, and no chance at all at anything approaching a normal life, given their need to be in a sterile environment at all times.

Analyses after the fact showed that the issue with the viral vectors used in the Paris and London trials was a combination of two factors. The vectors tended to integrate into other genes, near their beginning. And once they did, they would transactivate those genes; that is, the viral regulatory elements that were part of the vector would turn on not just the IL2RG gene, but also its new neighbors near the integration site.

Every so often, in turn, those new neighbors would be oncogenes, and the vector would lead to uncontrolled growth of the cells. Such integration was a rare event – but because the cells had a growth advantage, rare integration ultimately translated into a 25 percent chance of developing leukemia for the treated boys.

In the new trial, which is an international trial enrolling patients at multiple institutions, including the Hospital Necker Enfants Malade in Paris and the Great Ormond Street Hospital in London where the earlier gene therapy trials were conducted, the vectors "have the same gamma-retroviral backbone" as the earlier vectors, Pai said. But to keep those vectors from bothering their neighbors, that backbone has been combined with weaker regulatory elements taken from human cells.

One question was whether those weaker regulatory elements would still be able to turn on the IL2RG gene. But the results, Pai said, have been in line with the success rate observed in earlier trials.

So far, out of nine patients that have been treated, eight survived and seven have enough functioning T cells to fight off infections. The eighth surviving child received a cord blood transplant after the gene therapy was unsuccessful at reconstituting his immune system.

And genetic analyses of the T cells to date do not show any signs that there are certain cells that have a growth advantage of the kind that could ultimately develop into leukemia.

Pai said the team is still accruing patients to reach its planned size of 20. Longer-term, the researchers hope to combine their approach with low-dose chemotherapy, an approach they hope would lead to better reconstitution of B cells as well as T cells.

She noted that one advantage of the approach is that it can be used in patients with active infections, who can be so sick that other interventions are risky.

And, she added, the method can be used "for the many patients who don't have a matched donor available," which is the majority of patients. "It could potentially even supplant allogeneic transplants."