In this phase II randomized clinical study, Nishida et al. tested the combination of gemcitabine and a Wilms’ tumor gene 1 (WT1) peptide vaccine in patients with pancreatic ductal adenocarcinoma. The combination was well-tolerated. Although effects on overall survival were minimal, resulting in a failed primary endpoint, progression-free survival was significantly improved in patients with metastatic disease and in patients demonstrating a response to the vaccine (as measured by delayed type hypersensitivity positivity and increased WT1-specific cytotoxic T cells).
We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it to gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01- or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTLs). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival (PFS) (hazard ratio [HR], 0.66; P = 0.084) and improved overall survival rate at 1 year (1-year OS%) (GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well-tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared to the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86) (P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses.
Author Info: (1) Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine sumiyuki-n@imed3.med.osaka-u.ac.jp. (2) Department of Molecular Gastroe
Author Info: (1) Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine sumiyuki-n@imed3.med.osaka-u.ac.jp. (2) Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine. (3) Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science, Tohoku University. (4) Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine. (5) Surgery, Kansai Medical University. (6) Division of General and Gastroenterological Surgery, Department of Surgery, Toho University Faculty of Medicine. (7) Department of Gastroenterology, Sendai City Medical Center. (8) Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine. (9) Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine. (10) Department of Biostatistics, Yokohama City University. (11) Department of Biostatistics, Yokohama City University. (12) Cancer Immunotherapy, Osaka University Graduate School of Medicine. (13) Department of Cancer Immunology, Osaka University Graduate School of Medicine. (14) Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine. (15) Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine. (16) Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University. (17) Department of Surgery, Tohoku University Graduate School of Medicine. (18) Surgery, Kansai Medical University. (19) Division of General and Gastroenterological Surgery, Department of Surgery, Toho University Faculty of Medicine. (20) Department of Gastroenterology, Sendai City Medical Center. (21) Division of Oncology, Research Center for Medical Science, The Jikei University School of Medicine. (22) Cancer Stem Cell Biology, Osaka University Graduate School of Medicine. (23) Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine. (24) Department of Cancer Immunology, Osaka University Graduate School of Medicine.
