NIH TIL-TNF GENE THERAPY TRIALS BEGAN JAN. 29

NIH TIL-TNF GENE THERAPY TRIALS BEGAN JAN. 29 on two patients with advanced malignant melanoma, the National Cancer Institute announced. The protocol to study tumor infiltrating lymphocytes (TIL) that have been genetically altered to secrete tumor necrosis factor (TNF) for the treatment of malignant melanoma was submitted to FDA July 31 and approved in November ("The Pink Sheet" Nov. 19, T&G-7). The protocol allows treatment of up to 50 such patients. The delay in starting the trial was due to the resolution of several fine points with FDA in December and subsequently to the complexity and unpredictability of preparing genetically altered material for reinfusion in patients, NCI said. The study is using TNF vectors provided by Gene Therapeutics Institute and Cetus. The trial is being conducted by NCI Surgical Branch Chief Steven Rosenberg, MD/PhD, assisted by Deputy Branch Chief of Metabolism Michael Blaese, MD, and National Heart, Lung & Blood Institute Chief of Molecular Hematology W. French Anderson, MD. At a Dec. 13 meeting of FDA's Biological Response Modifiers Committee, NHLBI's Anderson said one safety concern about the TIL- TNF human trial is "the possibility of inducing a recombinant virus either in material that goes into the patient, or in the patient." However, "with the safety procedures now followed, the possibility . . . is reduced to near zero," he said. Another concern, Anderson told the advisory committee, is that only "something like 0.015%" of the TNF carrying cells actually reach the tumor, with the rest being trapped by the body, especially in the liver. Investigators have shown NIH and FDA that the risks of high TNF liver concentration are not significant, he reported. Anderson noted that "there is, however, one risk factor that remains, and that is the possibility of producing a tumor by an insertional event." In studies of 1,800 mice over six years and in 659 months of testing in monkeys, however, "there is not yet a single case that appears to be a tumor caused by a vector," Anderson pointed out. In 97.7 months of gene therapy in humans, consisting predominantly of the use of marker genes in 10 TIL patients, there have been "no side effects or evidence of any cancer or other toxicity produced by the gene transfer." The trial is the second therapeutic use of gene insertion to be studied at NIH. In September, a team led by Blaese began treating a four-year old victim of adenosine deaminase (ADA) deficiency with genetically altered lymphocytes. The preliminary results have been encouraging, Blaese said at the December committee meeting.