PHASE I STUDY OF IMMUNOTHERAPY OF MALIGNANT MELANOMA BY 
DIRECT GENE TRANSFER 
1.0 Background and Rationale 
1.1 Overview 
Cancer is a disease ir. which certain cells grow uncontrolled by the body's normal self- 
regulatory mechanisms. Traditional chemotherapy seeks to control cancer by killing 
rapidly dividing cells or by preventing cells from entering cell cycle and dividing. 
However, a number of non-malignant cells in the body such as bone marrow cells and 
intestinal epithelium cells, are also rapidly dividing and hence are highly susceptible to 
the toxicity of chemotherapy. Doses sufficient to induce remission in the cancer cannot 
be administered without life-threatening side effects in 5-10% of the patients and the 
overall mortcdity from chemotherapy is 0.5%. A therapeutic approach that selectively 
kills tumor cells with high efficacy would theoretically be far superior to currently 
available therapies. 
The goal of immunotherapy is to stimulate the immune system to recognize and kill 
cancer cells by modifying the tumor cells or modifying the host response by such 
mechanisms as expanding the lymphocytes that respond specifically to the antigens on 
the tumor cells. Immunotherapy has shown promise as an approach to the treatment of 
mailignancy. Indeed, cancers such as melanoma, renal ceU carcinoma and colon 
adenocarcinoma are responsive to modulation of immune function, becai;ise the 
immune system can be induced to recognize tumor associated and tumor specific 
antigens in these cells. 
Over the last several decades, there have been many attempts to identify tumor-specific 
cintigens that might be the targets for cytotoxic antibodies or cell-mediated immunity. 
There have been numerous attempts to develop vaccines and monoclonal antibodies 
directed at one or more preferentially expressed cell surface antigens in a variety of 
cancers. Overall, tumor vaccines using intact cells or extracts plus adjuvants have given 
about a 10-20% response rate. Other approaches to immunotinerapy have involved the 
administration of non-specific immunomodulating agents such as Bacillus Calmette- 
Guerin (BCG), cytokines, and/or adoptive transfer of cytotoxic T cells, which have 
shown promise in animal models (1-6) and in man (7-10). More recently, molecular 
genetic interventions have been designed in an attempt to improve the efficacy of 
immunotherapy. 
Nabel and colleagues at the University of Michigan are investigating a novel molecular 
genetic intervention for human malignancy that enhances the immune response to 
tumors by in vivo gene transfer. This immunotherapeutic approach based on animal 
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