Genetically marking human cells--results of the first clinical gene transfer studies

The rapid development of both knowledge and techniques in molecular biology have made it possible to engineer genetic constructs and transfer them into cells of individuals with various diseases. Such gene therapies may alleviate or perhaps even cure diseases for which no adequate treatment now exists. One potential application is to treat genetic disease by inserting a normal gene into cells in individuals with a "malfunctioning" gene. The added genetic information could allow these cells to function properly and might reduce or eliminate the sequelae of the disease. Such genetic manipulation could also be used to combat other diseases using the same general technique. For example in cancer patients, various cytokine genes inserted into tumor cells may serve as components of a tumor vaccine because such cytokine-secreting tumor cells can induce a significant T-cell response in experimental animal models when compared with non-gene-modified tumors, ultimately leading to a systemic immune response. In addition to treating patients, transferred genes also can serve as markers to obtain important information about the fate of otherwise indistinguishable cells. For example, we used a genetic marker to label tumor-infiltrating lymphocytes (TILs) to monitor their in vivo survival and ability to "home" to tumor sites. Gene markers also were transferred into autologous bone marrow cells to study the mechanism of tumor relapse. This review will focus primarily on studies using gene markers to track TILs after transfer. We will focus on the following issues: (a) that TILs are potent antitumor cells, mediating partial and complete responses in patients with melanoma; (b) the importance of the initial gene marked TIL study; (c) safety considerations in the use of gene marking/gene therapy; (d) results of gene-marked TIL studies; and (e) other gene-marked cells.