1.0 OBJECTIVES 
We plan to use retroviral vectors to transfer the gamma interferon (y-IFN) gene into cancer cells 
from melanoma patients. It is hoped that the resultant expression of y-IFN from the tumor cells 
will dramatically improve antigenic presentation by increasing the level of Class I major 
histocompatability complex (MHC) proteins that present antigen to the immune system. 
Additionally, subsequent tumor-specific cellular immune activation may also be improved by 
supplying this versatile lymphokine, y-IFN, crucial to the activation of immune cells that, in turn, 
are essential to combat human cancer. 
Short-term tumor cell lines from human melanoma biopsy material will be established. The cell 
cultures will then be transduced with the y-IFN retroviral vector. After selection for transduced 
cells by growth in the antibiotic, G418, the cells will be tested for sterility, lethally irradiated so 
that they can no longer divide, and the y-IFN-expressing autologous tumor cells will be injected 
back into the tumor biopsy donor. The study will determine safety, clinical response (tumor 
burden), and biological response (immune responses). The resultant increase in specific immunity 
against the now highly immunogenic gene-modified tumor cells may also result in a significant 
response against the endogenous, unmodified metastatic tumors. 
2.0 INTRODUCTION AND RATIONALE 
2.1 CANCER IMMUNOLOGY 
Host immunity is an important mechanism by which malignant tumors can be kept in check or 
even cleared. Established tumors are therefore under selective pressure to develop means of 
evading the immune system. Although the mechanisms by which tumors evade the immune 
system are undoubtedly varied and complex, at least one mechanism appears to derive from the fact 
that the levels of Class I MHC proteins are unusually low on most tumors (1, 2). Since Class I 
MHC proteins are essential for the presentation of intracellular antigen to the immune system (3, 
4), suboptimal levels of MHC proteins may prevent effective presentation of tumor-specific 
antigens. The immune system is therefore relatively blind to the tumor cell, at least with regard to 
MHC Class I-restricted cytotoxic T lymphocytes (CTL). A second mechanism by which tumors 
could evade the immune system is to generate suppressor T cells or other immune depressing 
substances to prevent the normal activation of potent anti-tumor immunity (immune "anergy")(5- 
7). An effective immunotherapy must necessarily overcome one or both of these phenomena. 
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