Treatment of Patients With Metastatic Melanoma With Autologous Tumor-Infiltrating Lymphocytes and Interleukin 2

Background: Studies of human tumor-infiltrating lymphocytes (TILs) derived from patients with a variety of histologic types of cancer have demonstrated that cellular immune reactions against established malignancy exist in humans. Purpose: We report the results of using autologous TILs plus high-dose bolus interleukin 2 (IL-2), with or without the concomitant administration of cyclophosphamide, in the treatment of 86 consecutive patients with metastatic melanoma. Methods: From May 1987 through December 1992, 86 patients (38 female and 48 male) with metastatic melanoma were treated (145 courses) with autologous TILs plus high-dose intravenous bolus IL-2 (720 000 IU/kg every 8 hours). TILs plus IL-2 were administered in two cycles separated by approximately 2 weeks. Two treatment cycles constituted one treatment course. Patients received a maximum of 15 doses of IL-2 per cycle given every 8 hours until grade 3 or 4 toxicity was reached that could not easily be reversed by standard supportive measures. All patients received concomitant medications to abrogate some of the side effects of IL-2 administration: acetaminophen (650 mg every 4 hours), indomethacin (50 mg every 8 hours), and ranitidine (150 mg every 12 hours). Fifty-seven of the 86 patients received a single intravenous dose of 25 mg/kg cyclophosphamide approximately 36 hours before receiving the first intravenous infusion of TILs plus IL-2. Six weeks after treatment, all known sites of disease were evaluated. Results: The overall objective response rate in these patients was 34% and was similar in patients receiving TILs and IL-2 alone (31%) or in conjunction with cyclophosphamide (35%). There was no significant difference in the objective response rate in patients whose therapy with high-dose IL-2 had failed (32%) compared with patients not previously treated with IL-2 (34%). The frequency of response to treatment was greater in those patients who were treated with TILs from younger cultures (P =.0001), TILs with shorter doubling times (P =.03), and TILs that exhibited higher lysis against autologous tumor targets (P =.0008). Patients who received TILs generated from subcutaneous tumor deposits had higher response rates (49%) compared with those receiving TILs from lymph nodes (17%; P =.006). There was one treatment-related death due to respiratory insufficiency. Conclusions: Treatment with TILs and IL-2 with or without cyclophosphamide can result in objective responses in about one third of patien