Adenosine deaminase deficiency

Early Results of Gene Therapy Encouraging

Less than months after she received the first federally approved infusion of genetically engineered cells to cure a disease, a young girl with a life-threatening immune deficiency shows signs of improvement, researchers reported last week. National Institute of Health (NIH) gene therapist W. French Anderson told an FDA panel that preliminary findings leave him "cautiously optimistic" the novel therapy is working.

But Anderson also told reporters that related studies, in which cancer patients will receive genetically enhanced tumor-killing cells, remain stalled because of a technical problems and because of a previously unpublicized "hold" placed on the procedure by some FDA revieweres who -- despite the agency's approval last month -- remain concerned about a potential risk of the experimental procedure.

Speaking before the FDA's Biological Response Modifiers Advisory Committee in Rockville, Md., Anderson and NIH co-worker R. Michael Blaese provided the first public progress report for a four-year-old girl with an inherited immune disrder called ADA deficiency (SN: 9/22/90, p.180). To date, she has received four infusions of gene-altered white blood cells. The researchers reported that for the first time in her life, the youngster's bloodstream now contains normal numbers of disease-fighting T cell, a kind of white blood cell normally destroyed in victims of ADA deficiency.

Anderson noted that her improved white cell count could not have resulted from the mere addition of the laboratory-reared cells; the number of white blood cells circulating in her body has doubled since she received a number of cells equal to about 10 percent of her original count. This suggests the engineered cells are somehow nurturing the girl's handicapped white blood cells, perhaps by secreting growth factors that her own cells cannot make.

Blaese says tests indicate the engineered cells, which live in the girl's circulation for at least three weeks after aach infusion, may have a survival advantage over ADA-crippled cells -- a finding researchers had hope to see. He says other measures of the girl's immune status, while "not discouraging," remain too preliminary to release. The girl remains healthy and a second child with the same disease may begin receiving the same treatment in January, Blaese says.

Clinical trials of a similar genetic therapy for malignant melanoma could begin within the next three weeks, Anderson told the FDA committee. But he also noted that the team performing the therapy, which is led by Steven A. Rosenberg of NIH and includes Anderson and Blaese, had experienced problems getting patients' gene-altered cells to grow properly in culture. The cells have been engineered to produce supplemental quantities of a naturally occurring cancer-fighting compound called tumor necrosis factor (TNF).

Anderson also revealed that the FDA's highly publicized "approval" of the cancer procedure in November included a proviso requiring the resolution of certain unanswered questions before the first infusions begin. As of this week, the FDA's hold remains in effect, Anderson told SCIENCE NEWS. He said the agency wants to know how much TNF produced by the engineered cells remains bound to those cells' outer membranes. Most of the altered cells get trapped and destroyed by the liver before ever reaching the tumor site, Anderson notes. He says some FDA reviewers worried that if large amounts of TNF remain bound to the membranes of cells captured by the liver, then toxic TNF concentrations could build up in that organ.

Jay J. Greenblatt, chief of the National Cancer Institute's drug regulatory affairs section, says the Rosenberg team this week provided the FDA with new evidence that very little TNF remains membrane bound, suggesting the therapy poses little risk of liver damage. He suspects the first infusion into cancer patients may begin during the first week of January.

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