2.3 Gene Transfer and Gene Therapy 
Retroviral-mediated gene transfer is being developed for the study and 
treatment of human disease (29,30), and the first clinical trials using this 
technology are in progress. In the first clinical trial, approved in January 
1989, a retroviral vector containing the bacterial gene for neomycin 
resistance (neoR) was used to mark tumor infiltrating lymphocytes (TIL) 
extracted from each patient's resected tumor. These TIL are then reinfused 
into the donor/patient in combination with IL-2 as immunotherapy for 
metastatic cancer (31). Since the vector-transduced TIL contain a unique 
genetic marker, the neoR gene, the in vivo distribution and longevity of the 
reinfused TIL can be studied (32,33). Reinfusion of these cells has been 
associated with objective responses in up to 40% of patients studied (34). 
Additional gene transfer experiments now in clinical trials include: Gene- 
marking neuroblastoma cells in the bone marrow of children subsequently 
undergoing autologous marrow transplant to determine if relapses are due to 
cells remaining in the body after chemotherapy or to neuroblastoma cells 
introduced with the "purged” autologous marrow; gene-marking CML cells in 
the bone marrow of patients undergoing bone marrow transplant to study the 
mechanism of relapse; gene-marking donor hepatocytes subsequently 
injected in the spleen or portal systems of patients in liver failure in the setting 
of partial liver transplant to evaluate the success of the procedure; as well as 
others. 
The first human gene therapy protocol was initiated in September, 
1990. In this study, patients with severe combined immunodeficiency (SCID) 
due to adenosine deaminase (ADA) deficiency are treated with infusions of 
autologous lymphocytes transduced with the ADA gene via a retroviral vector. 
To date, two patients have received this therapy. 
Gene transfer therapy for HIV infection has not yet been attempted. 
One group has reported on a mouse model demonstrating that expression of 
HIV genes introduced by a retroviral vector leads to induction of powerful 
cytotoxic T lymphocyte (CTL) responses (35). The required doses are 106 - 
10^ cells, and the responses are MHC class I restricted and mediated by CD8 
cells. These investigators noted that the cells administered are apparently 
destroyed by the response they generate. Other approaches for treatment of 
HIV infection have been proposed and include introducing into cells a gene 
that produces an enzyme capable of converting a prodrug into its active form. 
One group used a retroviral vector to introduce an HIV-inducible herpes 
simplex virus thymidine kinase (TK) gene into cells in culture followed by 
treatment with acyclovir (35,36). This approach proved to be very effective in 
selectively killing HIV-infected cells at otherwise nontoxic concentrations of 
drug. 
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