ABSTRACT
OBJECTIVE: The field of cancer vaccine therapy is currently expected to become the fourth option in the treatment of cancer after surgery, chemotherapy and radiation therapy. We developed a novel cancer peptide vaccine therapy for bladder cancer through a genome-wide expression profile analysis. METHODS: Among a number of oncoproteins that are transactivated in cancer cells, we focused on M phase phosphoprotein 1 and DEP domain containing 1, both of which are cancer-testis antigens playing critical roles in the growth of bladder cancer cells, as candidate molecules for the development of drugs for bladder cancer. In an attempt to identify the peptide epitope from these oncoantigens, we conducted a clinical trial using these peptides for patients with advanced bladder cancer. RESULTS: We identified HLA-A24-restricted peptide epitopes corresponding to parts of M phase phosphoprotein 1 and DEP domain containing 1 proteins, which could induce peptide-specific cytotoxic T lymphocytes. Using these peptides, we found that M phase phosphoprotein 1- and DEP domain containing 1-derived peptide vaccines could be well tolerated without any serious adverse events, and effectively induced peptide-specific cytotoxic T lymphocytes in vivo. CONCLUSIONS: The novel approach adopted in the treatment with peptide vaccines is considered to be a promising therapy for bladder cancer.
Subject(s)
Antigens, Neoplasm/immunology , Cancer Vaccines/therapeutic use , Dendritic Cells , Kinesins/immunology , Kinesins/therapeutic use , Receptor-Like Protein Tyrosine Phosphatases, Class 3/therapeutic use , T-Lymphocytes, Cytotoxic/immunology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Adjuvants, Immunologic/administration & dosage , Adult , Aged , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , DNA, Complementary/analysis , DNA, Neoplasm/analysis , Drug Administration Schedule , Female , Freund's Adjuvant/administration & dosage , Gene Expression Profiling , Genome-Wide Association Study , Humans , Immunohistochemistry , Kinesins/administration & dosage , Laser Capture Microdissection , Male , Middle Aged , Peptides , Protein Array Analysis , Receptor-Like Protein Tyrosine Phosphatases, Class 3/administration & dosage , Receptor-Like Protein Tyrosine Phosphatases, Class 3/immunology , T-Lymphocytes, Cytotoxic/drug effects , Treatment Outcome , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgeryABSTRACT
Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. Immunotherapy using epitope peptide for VEGFR2 (VEGFR2-169) that we identified previously is expected to improve the clinical outcome. Therefore, a phase I clinical trial combining of VEGFR2-169 with gemcitabine was conducted for patients with advanced pancreatic cancer. Patients with metastatic and unresectable pancreatic cancer were eligible for the trial. Gemcitabine was administered at a dose of 1000 mg/m(2) on days 1, 8, and 15 in a 28-day cycle. The VEGFR2-169 peptide was subcutaneously injected weekly in a dose-escalation manner (doses of 0.5, 1, and 2 mg/body, six patients/one cohort). Safety and immunological parameters were assessed. No severe adverse effect of grade 4 or higher was observed. Of the 18 patients who completed at least one course of the treatment, 15 (83%) developed immunological reactions at the injection sites. Specific cytotoxic T lymphocytes (CTL) reacting to the VEGFR2-169 peptide were induced in 11 (61%) of the 18 patients. The disease control rate was 67%, and the median overall survival time was 8.7 months. This combination therapy for pancreatic cancer patients was tolerable at all doses. Peptide-specific CTL could be induced by the VEGFR2-169 peptide vaccine at a high rate, even in combination with gemcitabine. From an immunological point of view, the optimal dose for further clinical trials might be 2 mg/body or higher. This trial was registered with ClinicalTrial.gov (no. NCT 00622622).
Subject(s)
Cancer Vaccines/therapeutic use , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/therapy , Peptide Fragments/immunology , Vascular Endothelial Growth Factor Receptor-2/immunology , Adult , Aged , Combined Modality Therapy , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/mortality , Peptide Fragments/therapeutic use , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Regulatory/immunology , Vascular Endothelial Growth Factor Receptor-2/therapeutic use , GemcitabineABSTRACT
The tom2-1 mutation of Arabidopsis thaliana reduces the efficiency of intracellular multiplication of tobamoviruses. The tom2-1 mutant was derived from fast-neutron-irradiated seeds, and the original mutant line also carries ttm1, a dominant modifier that increases tobamovirus multiplication efficiency in a tobamovirus-strain-specific manner in the tom2-1 genetic background. Here, we show that the tom2-1 mutation involved a deletion of approximately 20 kb in the nuclear genome. The deleted region included two genes named TOM2A and TOM2B that were both associated with the tom2-1 phenotype, whereas ttm1 corresponded to the translocation of part of the deleted region that included intact TOM2B but not TOM2A. TOM2A encodes a 280 amino acid putative four-pass transmembrane protein with a C-terminal farnesylation signal, while TOM2B encodes a 122 amino acid basic protein. The split-ubiquitin assay demonstrated an interaction of TOM2A both with itself and with TOM1, an integral membrane protein of A.thaliana presumed to be an essential constituent of tobamovirus replication complex. The data presented here suggest that TOM2A is also an integral part of the tobamovirus replication complex.