in this area has been the cloning of the gene that encodes a mouse tumor antigen 
recognized by cytotoxic T cells and the identification of its mutation (53). The 
same approach is now being applied to human melanoma, and a gene encoding 
an antigen recognized by cytolytic T cells on a human melanoma has been 
identified. In this case, the antigen appears to be presented by HLA-A1 (57). 
2.3 Biologic effects in vitro of Interleukin-2 
Interleukin-2 is a lymphokine that is produced by T helper cells and stimulates T 
cells, B cells and natural killer (NK) cells. In vitro studies, IL-2 has been shown 
to induce proliferation of antigen-specific T cells. Helper, cytotoxic, and 
suppressor T cells from melanoma patients have been grown in vitro by culturing 
in the presence of IL-2 and antigen-presenting cells (21). B cell responses in 
vitro have also been enhanced by IL-2 (22). Growth of T cells in IL-2 can also 
lead to secretion by T cells of other lymphokines, including interferon- 7 , IL-1, 
IL-4, IL- 6 , GM-CSF and TNF-a. 
2.4 Interleukin-2 in Human Studies 
A number of investigators have studied the systemic administration of IL-2 
patients with advanced cancer (11-13). Systemic IL-2 has shown modest activity 
in patients with advanced melanoma and other tumors, with a 15-20% response 
rate reported (12). The major effect of IL-2 appears to be the expansion of 
effector cell populations that have the capability to kill the tumors in vitro. 
However, because of the short serum half-life of IL-2, high doses have been used 
that are very toxic. Hypotension and capillary leak syndrome with decreased 
systemic vascular resistance has led to interstitial pulmonary edema, prerenal 
azotemia, cardiac arrhythmias, and myocardial infarction (11-13). 
2.5 Gene Transfer in Animal Models 
Several laboratories have shown that the introduction of cytokine genes, such as 
IL-2(14,16), IL-4 (31), IFN -7 (32,15), TNF-a (33) and GM-CSF (34) into tumor 
cells leads to their rejection by an immunologically competent host in specific 
animal model systems. Secretion of GM-CSF or IL-4 by tumor cells has led to 
localized inflammatory responses at the tumor site without apparent induction of 
immunological memory (31,34). Initial studies by Tepper et al (31) demonstrated 
that localized IL-4 secretion at the tumor site was characterized by an 
accumulation of eosinophiles and macrophages. IL-2, interferon- 7 , and TNF-a 
on the other hand have induced long lasting cellular immune responses that led to 
rejection of potentially lethal tumor challenges at later time points (15,31,32). 
Fearon et al (16) introduced the IL-2 gene into a poorly immunogenic murine 
colon carcinoma. The IL-2-secreting tumors were rejected, and subsequently 
induced an effective cytolytic T cell response. Depletion of CD 8 -positive cells in 
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