Immunization by particle-mediated transfer of the granulocyte-macrophage colony-stimulating factor gene into autologous tumor cells in melanoma or sarcoma patients: report of a phase I/IB study.

The primary objective of this phase I study was to determine the safety of an autologous tumor vaccine given by intradermal injection of lethally irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected autologous melanoma and sarcoma cells. Secondary objectives included validation of the gene delivery technology (particle-mediated gene transfer), determining the host immune response to the tumor after vaccination, and monitoring patients for evidence of antitumor response. Sixteen patients were treated with either of two different doses of GM-CSF-treated tumor cells. One patient received treatment with both doses of tumor cells. No treatment-related local or systemic toxicity was noted in any patient. Patients administered 100% treated cells (i.e., with a preparation of tumor cells that had all been exposed to GM-CSF DNA transfection) had a more extensive lymphocytic infiltrate at the vaccine site than did patients given 10% treated cells (a preparation of tumor cells in which 10% had been exposed to GM-CSF transfection) or nontreated tumor. The generation of a systemic immune response to autologous tumor by a delayed-type hypersensitivity response to the intradermal placement of nontransfected tumor cells was noted in one patient. One patient had a transient partial response of metastatic tumor sites. The entire procedure, from tumor removal to vaccine placement, was accomplished in less than 6 hr in all patients. Four of 17 patient tumor preparations produced greater than 3.0 ng of GM-CSF per 10(6) cells per 24 hr in vitro. The one patient with greater than 30 ng of GM-CSF per 10(6) cells per 24 hr in vitro had positive DTH, a significant histologic inflammatory response, and clinically stable disease. This technique of gene transfer was safe and feasible, but resulted in clinically relevant levels of gene expression in only a minority of patients.

Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival.

PURPOSE: Based on preclinical and clinical studies that suggested amifostine may potentiate the effects of cytotoxic drugs, we conducted a phase II trial of amifostine, cisplatin, and vinblastine (ACV) in patients with metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with metastatic NSCLC received amifostine (740 or 910 mg/m2) before 120 mg/m2 of cisplatin on day 1, plus weekly 5 mg/m2 of vinblastine without amifostine. Cycles were repeated every 4 weeks. Patients were required to have good performance status, no prior chemotherapy or biologic therapy, adequate organ function, and measurable disease. RESULTS: Sixteen of 25 assessable patients had an objective response documented by computed tomographic (CT) scan (64%; 95% confidence interval, 45% to 85%). With a median duration of follow-up of 19.2 months, the estimated median survival is 17 months and 1-year survival is 64% (+/- 10%). Toxicities included grades 3 and 4 neutropenia (8% and 92%, respectively) and nausea and vomiting (32% and 4%, respectively). Reversible grade 3 nephrotoxicity occurred in 12% of patients, although only one of 13 patients (7%) who received > or = four cycles of therapy had > or = 40% reduction in creatinine clearance. Grade 3 neuropathy was observed in seven patients at cumulative cisplatin doses that ranged from 324 to 660 mg/m2; grade 3 ototoxicity occurred in three patients at cumulative cisplatin doses that ranged from 390 to 450 mg/m2. Four patients (16%) required early stopping of an amifostine infusion due to hypotension. CONCLUSION: ACV appears to be a highly active regimen in metastatic NSCLC. Acute toxicities were generally reversible and the data suggest that amifostine may protect against long-term renal insufficiency from cumulative doses of cisplatin. Although the sample size of this trial is small, the results are significantly encouraging to warrant confirmation in randomized multiinstitutional trials.