Patient-specific vaccines derived from autologous tumor cell lines as active specific immunotherapy: results of exploratory phase I/II trials in patients with metastatic melanoma.

Seventy-four (74) patients with metastatic melanoma were treated with patient-specific vaccines derived from autologous tumor cell lines. Cryopreserved irradiated tumor cells were injected weekly for 3 weeks, then monthly for 5 months. At a median follow up >6 years, the median event-free survival (EFS) was 4.5 months, with 13 patients alive and progression free 6-12 years later. Median overall survival (OS) was 20.5 months, with 29% 5-year OS. Tumor response rate was 9% among the 35 patients with evaluable disease who received at least 3 injections. Better survival was observed for patients who had minimal rather than clinically evident metastatic disease at the time vaccine therapy was initiated (5-yr OS 47% vs. 13%; p < 0.0001), received granulocyte-macrophage colony-stimulating factor and/or interferon gamma as an adjuvant (5-yr EFS 26% vs. 0%; p < 0.0001) or received an average of <7 million cells for each of the first 3 injections, compared to those who received 7-11.9 million or >12 million cells per injection (5-yr EFS OS 35% vs. 24%; p = 0.041 and p = 0.034). There was a trend toward better EFS for those who had a positive delayed type hypersensitivity (DTH) reaction to an intradermal injection of 1 million irradiated tumor cells at baseline, or converted to positive after 3 injections, compared to those whose DTH remained negative (5-yr EFS 39% vs. 18%; p = 0.159). This treatment approach is feasible, produces minimal toxicity, and is associated with longterm survival in a significant proportion of patients.

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.

High-dose chemotherapy and autologous stem cell rescue for metastatic breast cancer: superior survival for tandem compared with single transplants.

During 1990-1999, we treated 60 patients with breast cancer who had distant metastases with high-dose chemotherapy and autologous stem cell rescue (HDC) after they had responded to induction chemotherapy. HDC regimens were MiTepa (60 mg/m2 mitoxantrone by continuous intravenous infusion over 3 days plus 300 mg/m2 thiotepa intravenously over 2 hours daily x 3 days) and ICE (12 g/m2 ifosfamide, 1800 mg/m2 carboplatin, 2 g/m2 etoposide; all 3 by continuous intravenous over 4 days). At a median follow up >8 years, the median failure-free survival (FFS) was 13.9 months, median overall survival (OS) 29.1 months, 5-year FFS 12%s and 5-year OS 25%. Thirty-three patients underwent tandem (T) transplants; 27 underwent a single (S) HDC. Median ages for these 2 groups were 45 and 48 years; bone and liver metastases were more prevalent in the T cohort, whereas lung metastases were more prevalent in the S cohort. At a median follow up of 6.5 years for the S group and >9 years for the T group, there were 52 deaths. FFS was better for T: median 15.7 versus 7.7 months (p2 = 0.010) as was OS: median 32.7 versus 17.7 months, 2-year survival 68% versus 41%, and 5-year survival 32% versus 15% (p2 = 0.010). As a group, patients with distant metastatic breast cancer who underwent tandem transplants had a better posttransplant survival than patients who underwent a single HDC.

Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma.

This study was performed to obtain safety and survival data for patients with histologically confirmed recurrent glioblastoma multiforme (GBM) who received intralesional lymphokine-activated killer (LAK) cells following surgery. LAK cells were generated by incubating peripheral blood mononuclear cells with interleukin-2 for 3 to 5 days in vitro. Forty patients with pathologic confirmation of GBM at surgery had placement of autologous LAK cells into the tumor cavity. The 23 men and 17 women had a median age of 48 years (range 21-76). The median interval from the original diagnosis of glioma to LAK treatment was 10.9 months. Patients received an average of 2.0 +/- 1.0 x 10(9) LAK cells, with viability of 91 +/- 6.8%. Treatment was well tolerated; there was one death within 60 days. At a median follow-up of 2.3 years, median survival post-LAK was 9.0 months; 1-year survival was 34%. Gender, age, location of tumor, LAK cell lytic activity, number of cells implanted, and inclusion of interleukin-2 at cell instillation were not correlated with outcome. Median survival from the date of original diagnosis for 31 patients who had GBM at initial diagnosis was 17.5 months versus 13.6 months for a control group of 41 contemporary GBM patients (p2 = 0.012). This treatment is safe and feasible. The median survival rates are higher than reported in most published series of patients who underwent reoperation for recurrent GBM. A randomized trial would be needed to establish therapeutic benefit.