Phase 1 trial of Wilms tumor 1 (WT1) peptide vaccine and gemcitabine combination therapy in patients with advanced pancreatic or biliary tract cancer.

An open-labeled, dose-escalation phase 1 trial of Wilms tumor 1 (WT1) vaccine and gemcitabine (GEM) combination therapy for patients with advanced pancreatic cancer or biliary tract cancer was performed. The primary end point was evaluation of toxicity, safety, and optimal immunologic dose of vaccine. Human leukocyte antigen (HLA)-A 0201, HLA-A 0206, and/or HLA-A 2402-positive patients with inoperable advanced pancreatic or biliary tract cancer who had not previously been treated with GEM were eligible for this study. Six doses of GEM and 4 doses of WT1 peptide (1 or 3 mg) emulsified in Montanide adjuvant were administered over 2 months. Twenty-five patients (13 male and 12 female) were enrolled. Nine patients had inoperable advanced pancreatic cancer, 8 had gallbladder cancer, 4 had intrahepatic, and 4 had extrahepatic bile duct cancer. The adverse events were comparable to those with GEM alone. Delayed-type hypersensitivity test was positive after vaccination in 2 patients, and WT1-specific T cells in peptide-stimulated culture were detected by tetramer assay in 59% (13 of 22) of patients. The disease control rate at 2 months was 89% for pancreatic cancer and 50% for biliary tract cancer. With a median follow-up time of 259 days, the median survival time for biliary tract cancer was 288 days, and that for pancreatic cancer was 259 days. Although objective clinical efficacy was not apparent, the safety of WT1 vaccine and GEM combination therapy was confirmed in this study.

Long-term administration of Wilms tumor-1 peptide vaccine in combination with gemcitabine causes severe local skin inflammation at injection sites.

The skin toxicity of vaccine therapy at injection sites is generally limited to Grades 1-2 due to the nature of their function. We experienced two cases of severe and prolonged local adverse effects in 25 patients following a Phase I study of gemcitabine and Wilms tumor-1 peptide vaccine mixed with incomplete Freund's adjuvant for inoperable pancreatic or biliary tract cancer. These patients requested to continue the treatment after the study period; however, in the course of compassionate use, they developed unacceptable local skin reactions and terminated their vaccine treatment. One patient (human leukocyte antigen, A0201, 3 mg) developed Grade 3 ulceration at the 10th vaccination and another (human leukocyte antigen, A2402, 1 mg) developed Grade 2 indulation and fibrosis at the 16th vaccination. Skin toxicity occurred at 6.4-8.4 months and continued for several months after the final vaccination during gemcitabine treatment. In these cases, activation or induction of Wilms tumor-1-specific T lymphocytes was not apparent in the peripheral blood despite their severe local reactions. Therefore, we need to monitor patients for late-onset, severe and long-lasting skin reactions at injection sites in Wilms tumor-1 cancer vaccine therapy, particularly for combination treatment with gemcitabine.

The strategy of immune globulin resistant Kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy.

BACKGROUND: We compared the clinical utility of additional intravenous immune globulin (IVIG) therapy with the clinical utility of steroid pulse therapy in patients with IVIG-resistant Kawasaki disease. METHODS: We enrolled 164 patients with Kawasaki disease who were treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Twenty-seven of these patients (16%) were resistant to the initial IVIG treatment. We compared the effectiveness of treatment strategies for the initial IVIG-resistant 27 patients, 14 of these patients were treated with additional IVIG therapy, and the other 13 patients were treated with steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3 days). RESULTS: Three patients in the group receiving additional IVIG treatment had coronary artery aneurysms (21.4%), no patients had coronary artery aneurysm in the steroid pulse therapy group; the difference in the incidence of coronary artery aneurysm was not statistically significant. The duration of high fever after additional treatment in the steroid pulse therapy group (1 ± 1.3 days) was significantly shorter than that in the additional IVIG treatment group (3 ± 2.4 days; P < 0.05). The medical costs were significantly lower in the steroid pulse therapy group than in the additional IVIG treatment group. CONCLUSION: Steroid pulse therapy was useful to reduce the fever duration and medical costs for patients with Kawasaki disease. Steroid pulse therapy and additional IVIG treatment were not significantly different in terms of preventing the development of coronary artery aneurysm.