I. Introduction 
In 1991, approximately 32,000 new cases of melanoma and 6500 deaths from 
metastatic melanoma were reported in the United States (reviewed, 1). The 
incidence has been increasing steadily in the last several decades, and by the 
year 2000, it is estimated that 1 in 90 individuals may develop melanoma 
during their lifetime. Although most lesions are curable by surgical resection 
at the time of diagnosis, if the disease metastasizes to regional lymph nodes 
or beyond, the prognosis for long-term survival is poor. Patients with 
metastases beyond the regional lymph nodes generally have a median survival of 
less than 12 months and 5-year survival rates of approximately 5%. 
Unfortunately, treatment for metastatic melanoma has been ineffective. DTIC 
and cisplatin are probably the most active single chemotherapeutic agents with 
objective response rates between 10-20%. Although some combination 
chemotherapy regimens produce response rates up to 50%, most of the responses 
are partial rather than complete and have a median duration of less than 6 
months. No treatment regimen appears to have prolonged median survival for 
patients with metastatic disease. In order to improve the outcome of patients 
with metastatic melanoma, novel approaches will be required. A current area 
of intense investigation is the application of agents that enhance host- 
mediated immune responses directed against this tumor. 
The potential for developing successful immunotherapies for melanoma has been 
demonstrated in preclinical and clinical studies of interleukin-2 (IL-2). IL- 
2 was shown to activate peripheral blood lymphocytes (PBL) in vitro, producing 
a population of cells called lymphokine-activated killer cells (LAK) that were 
able to kill both autologous and allogeneic fresh tumors and tumor cell lines 
(reviewed, 2) . The subset of lymphocytes with lytic capacity was primarily 
derived from natural killer precursors, expressed the CD56 antigen, and had 
minimal lytic activity against normal cells. When IL-2 was administered with 
LAK cells to tumor-bearing mice, the combination demonstrated potent antitumor 
activity. Based on these data, clinical trials of IL-2 and LAK cells were 
initiated in patients with metastatic melanoma, resulting in a few durable 
remissions and overall response rates in the range of 15-20% (3,4). 
Subsequent studies showed that high doses of IL-2 alone could produce similar 
response rates (5,6,7). The results of these studies confirmed that an agent 
such as IL-2 could produce tumor regression in some patients with advanced 
disease . 
In order to understand the reasons for treatment failure in the majority of 
patients, attempts were made to further define the mechanisms responsible for 
IL-2's antitumor activity in vivo. Although endogenous or adoptively 
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