NIH TIL/GENE MARKER STUDY DESIGN JUSTIFIES ADDITIONAL RISK

NIH TIL/GENE MARKER STUDY DESIGN JUSTIFIES ADDITIONAL RISK to patients, FDA Vaccines and Related Biological Products Advisory Committee concluded at a special Dec. 19 meeting. The committee voted unanimously that preclinical data supporting the safety of the first proposed use of retroviral mediated gene markers in humans are adequate for IND approval. The National Institutes of Health is looking for final FDA approval of the IND in January, with clinical trials anticipated to start by the end of March. The committee met to review safety issues related to the IND protocol for the use of a gene-marked tumor-infiltrating lymphocyte (TIL) that was submitted to FDA in October by National Heart Lung Blood Institute Chief of Molecular Hematology W. French Anderson, MD, and National Cancer Institute Chief of Surgery Steven Rosenberg, MD. TIL cells used in conjunction with IL-2 for the treatment of metastatic melanoma have been the focus of studies conducted by Rosenberg at NCI. The protocol calls for retroviral-mediated gene transfer, using a retroviral vector N2 and the neomycin resistant gene (NeoR), as a means of permanently labeling TIL cells in vivo to monitor TIL cell efficacy and to determine sites and duration of action in the body. In the study, ten patients with advanced cancer will be infused with the labeled TIL cells, which will be recovered subsequently from the patients and analyzed. The aim of the study is to "gain information about the distribution and survival of TIL in patients ... in order to optimize TIL immunotherapy," according to the study protocol. FDA announced the advisory committee meeting in a Dec. 12 Federal Register notice, giving less than the standard 15 days public notice. The notice explained that the committee meeting "involves an expedited review of a biologic intended for a life-threatening illness, consistent with FDA's new initiative for expediting the review of such products." The protocol, which has been reviewed by a total of seven committees, cleared the NIH Biosafety Committee in July and received final approval from the National Heart, Lung & Blood Institute's Internal Review Board on Dec. 20. Final approval from NIH's Recombinant DNA Advisory Committee (RAC), which has already given preliminary approval, is still pending. Questions raised by FDA Center of Biologics and Review and addressed by the committee related to the adequacy of preclinical data presented by the NIH researchers, the possibility of inadvertantly introducing replication-competent retroviruses into humans, the risk-to-benefit ratio of such a study, and future introductions of alternative vectors into the protocol. Describing the risks of the study, the protocol notes that retroviruses can "induce neoplastic disease by a process of insertional mutagenesis [and] there is a remote but finite probability that an occasional insertion will be in a location that could activate a proto-oncogene." Animal studies, the protocol adds, have not "shown any evidence of neoplasia after as long as two-and-one-half years of observation." At the meeting, the investigators pointed out that the proposed gene transfer studies could provide valuable information for future gene therapy and noted that animal studies are underway using Tumor Necrosis Factor, gamma interferon, IL-2 genes, and soluble CD4 for the treatment of AIDS.