Does continuous-infusion interleukin-2 increase survival in metastatic melanoma?

Pharmacy logbooks and clinical trial records were used to identify all 60 patients with metastatic melanoma who were treated as inpatients with intermediate-dose, continuous-infusion interleukin-2 (IL-2) in Hoag Hospital during 1987 to 1998. The hospital tumor registry was used to identify contemporary controls who had not received inpatient IL-2, matched for having distant metastatic melanoma, and by year and stage at original diagnosis, gender, and age. The mean time from original diagnosis to the documentation of distant metastatic disease was similar in both groups, 24 to 26 months. From the date of starting IL-2 therapy, patients had a median survival of 8.8 months, 38% 1-year survival, and 20% 5-year survival, with 8 patients alive beyond 5 years. However, there was no difference in survival from the first date of distant metastatic disease (median 25.8 months for IL-2 versus 31.5 months for controls, with survival rates 5 years after metastatic disease of 26% versus 31%). There was also no difference in overall survival from the date of original diagnosis (60.1 months for the IL-2 group versus 86.3 months for controls, with 5-year survival rates of 51% versus 64%, and 10-year survival rates of 29% versus 33%). This single-institution study failed to establish a survival advantage for patients with metastatic melanoma who received intermediate-dose, continuous-infusion IL-2 administered in the inpatient setting, compared to contemporary, matched-control patients who never received inpatient IL-2 therapy. However, the 5-year survival rates after a diagnosis of distant metastatic disease were a surprisingly high 26% to 31% in both groups. In the absence of a control group, the survival impact of IL-2 has probably been overestimated from single-arm phase II and III trials.

Treatment of human solid malignancies with autologous activated lymphocytes and cimetidine: a phase II trial of the cancer biotherapy research group.

OBJECTIVE: The Cancer Biotherapy Research Group conducted a clinical trial to verify encouraging reports of antitumor activity of autolymphocyte therapy. PATIENTS AND METHODS: Patients with a variety of advanced solid malignancies underwent an initial leukapheresis procedure to collect about 5 x 10(9) autologous lymphocytes that were stimulated in vitro for 3 days with anti-CD3 monoclonal antibody in the presence of indomethicin and cis-retinoic acid to obtain media that was frozen in aliquots. This media contained significant amounts of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon-gamma, and IL6, but no IL-2. Subsequently patients underwent up to 6 monthly leukaphereses to collect 2-5 x 10(9) autologous lymphocytes that were incubated in vitro for 6 days in the cryopreserved media containing autologous lymphokines, resulting in a cell population enriched for noncytotoxic T-helper lymphocytes. These were administered intravenously monthly for up to 6 months with daily oral cimetidine at a dose of 600 mg po qid, which was given throughout the treatment period. Tumor response was assessed every 2 months. RESULTS: There were 47 patients (25 women and 22 men) with a median age of 55 years (range 31-79). One hundred seventy four treatments were delivered and were well tolerated. A mean of 2.05 +/- 1.46 (range 0.82-12.8 x 10(9)) cells were infused. Eighty-five percent received two or more doses; 19% received six doses. Objective tumor responses were observed in 1/15 renal cell, 1/13 colorectal, 0/6 breast, 0/5 lung, 0/2 gastric, 0/2 sarcoma, 0/1 pancreas, 0/1 prostate, 0/1 melanoma, and 0/1 eccrine. Forty-three patients have died. Median survival was 8.8 months, 1-year survival 35%, and 2-year survival 15%. CONCLUSION: This complex treatment program was feasible. Infusion of these cells was well tolerated. Some antitumor activity was seen in patients with renal cell cancer and colorectal cancer.

Irradiated cells from autologous tumor cell lines as patient-specific vaccine therapy in 125 patients with metastatic cancer: induction of delayed-type hypersensitivity to autologous tumor is associated with improved survival.

OBJECTIVE: We established short-term cultures of pure tumor cells for use as autologous tumor cell vaccines in an effort to study the effects of patients-specific immunotherapy. PATIENTS AND METHODS: Surgically resected fresh tumor was obtained from patients with metastatic cancer. Successful tumor cell lines (5 x 10(7)) were expanded to 10(8) cells, irradiated, and cryopreserved for clinical use. Following a baseline test of delayed-type hypersensitivity (DTH) to an i.d. injection of 10(6) irradiated autologous tumor cells, patients received 3 weekly s.c. injections of 10(7) cells, had a repeat DTH test at week-4, then received monthly vaccinations for 5 months. A positive DTH test was defined as > or = 10 mm induration; survival was determined from the first DTH test. RESULTS: Short-term cell lines were successfully established for 299/695 patients (43%). Vaccines were prepared for 231 patients, 142 of whom were treated, and 125 had a baseline DTH test recorded. Median follow up at the time of analysis was greater than 5 years. There was no difference in survival for any of the following: gender, age > 50 years, melanoma histology, anergy to common recall antigens or baseline DTH test result. Only 17 patients had a positive DTH at baseline (14%), but DTH converted from negative to positive in 31/80 (39%) of those who were tested, and in 31/108 (29%) of all patients (intent-to-convert analysis). For the 48 patients who were DTH-positive at entry, or converted to DTH-positive, the median survival was 30.5 months and 5-year survival 41% compared to 11.4 months and 9% 5-year survival for 77 patients whose DTH was never positive (P2 = 0.003). However, survival was even better for patients whose DTH test converted to positive compared to patients who were DTH-positive at baseline (median 37.5 vs 11.9 mos, P2 = 0.066). CONCLUSION: This patient-specific, cell culture-derived, autologous tumor cell vaccine induced anti-tumor immune reactivity that was associated with improved survival in patients with advanced cancer.