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Turner A.M.,University of Birmingham | McGowan L.,University of Birmingham | Millen A.,NHS England | Rajesh P.,NHS England | And 7 more authors.
European Respiratory Journal

Vitamin D stimulates transcription of antiangiogenic and apoptotic factors that may suppress tumours, while vitamin D binding protein (DBP) may be a biomarker in murine lung cancer models. We sought to ascertain whether the vitamin D axis is altered in lung cancer or influences prognosis. 148 lung cancer patients, 68 other intrathoracic cancer patients and 33 noncancer controls were studied for up to 5 yrs. Circulating DBP and vitamin D levels were compared between groups and their effect on survival assessed by Cox regression analysis. Expression of DBP and vitamin D receptor (VDR) was examined in lung cancer cell lines and in normal and tumour lung tissue by Western blot and immunohistochemistry. Low serum DBP levels predicted lung cancer-specific death (p=0.04), and DBP was poorly expressed in lung cancer cells on Western blot and immunohistochemistry. Vitamin D did not predict cancer survival and VDR expression was variable in tumours. Preservation of serum DBP is a significant independent factor associated with better cancer outcome in operated lung cancer patients. Given the established role of DBP in macrophage activation and clearance of abnormal cells, further study on its involvement in lung cancer is merited. Source

Murao A.,Allergy and Rheumatic Diseases | Oka Y.,Allergy and Rheumatic Diseases | Tsuboi A.,Cancer Immunotherapy | Tanaka-Harada Y.,Allergy and Rheumatic Diseases | And 12 more authors.
Cancer Science

In tumor-bearing patients, tumor-associated antigen (TAA)-specific CTLs are spontaneously induced as a result of immune response to TAAs and play an important role in anti-tumor immunity. Wilms' tumor gene 1 (WT1) is overexpressed in various types of tumor and WT1 protein is a promising pan-TAA because of its high immunogenicity. In this study, to clarify the immune response to the WT1 antigen, WT1-specific CD8+ T cells that were spontaneously induced in patients with solid tumor were comparatively analyzed in both bone marrow (BM) and peripheral blood (PB). WT1-specific CD8+ T cells more frequently existed in BM than in PB, whereas frequencies of naïve (CCR7+ CD45RA+), central memory (CCR7+ CD45RA-), effector-memory (CCR7- CD45RA-), and effector (CCR7- CD45RA+) subsets were not significantly different between BM and PB. However, analysis of these subsets for the expression of CD57 and CD28, which were associated with differentiation, revealed that effector-memory and effector subsets of the WT1-specific CD8+ T cells in BM had less differentiated phenotypes and more proliferative potential than those in PB. Furthermore, CD107a/b functional assay for WT1 peptide-specific cytotoxic potential and carboxyfluorescein diacetate succinimidyl ester dilution assay for WT1 peptide-specific proliferation also showed that WT1-specific CD8+ T cells in BM were less cytotoxic and more proliferative in response to WT1 peptide than those in PB. These results implied that BM played an important role as a secondary lymphoid organ in tumor-bearing patients. Preferential residence of WT1-specific CD8+ T cells in BM could be, at least in part, explained by higher expression of chemokine receptor CCR5, whose ligand was expressed on BM fibroblasts on the WT1-specific CD8+ T cells in BM, compared to those in PB. These results should provide us with an insight into WT1-specific immune response in tumor-bearing patients and give us an idea of enhancement of clinical response in WT1 protein-targeted immunotherapy. © 2010 Japanese Cancer Association. Source

Homma S.,The DNA Medicine Institute | Morita S.,Yokohama City University | Morimoto S.,Allergy and Rheumatic Diseases | Hara K.,Osaka University | And 13 more authors.
Journal of Immunotherapy

Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02- restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity- positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy. © 2014 by Lippincott Williams and Wilkins. Source

Ogata A.,Allergy and Rheumatic Diseases | Ogata A.,Osaka University | Yoshida Y.,Allergy and Rheumatic Diseases | Morishima A.,Allergy and Rheumatic Diseases | And 4 more authors.
Proteomics Research Journal

Rheumatoid arthritis (RA) is a disease characterized by chronic synovial inflammation, leading to bone and cartilage destruction. An autoimmune process of unknown etiology is important in RA pathogenesis. Particularly, IL-6 plays a key role in RA pathogenesis. Therefore, interfering IL-6 signaling is important for treating RA. A humanized anti-IL-6 receptor monoclonal antibody, tocilizumab (TCZ), is now used as an innovative biological agent for the treatment of RA in more than 90 countries. TCZ is well tolerated and efficacious in patients with RA who are naïve to treatment and who have an inadequate response to disease-modifying antirheumatic drugs (DMARDs), methotrexate (MTX), and tumor necrosis factor inhibitors (TNFi). The general efficacy and safety profile of TCZ is comparable with that of TNFis. In contrast to TNFi, TCZ monotherapy is not inferior to TCZ combination therapy with MTX. This review summarizes the recent developments and available data supporting the use of TCZ as a possible first-line biological agent for treating RA. © Nova Science Publishers, Inc. Source

Lin Y.,Allergy and Rheumatic Diseases | Fujiki F.,Osaka University | Katsuhara A.,Osaka University | Oka Y.,Allergy and Rheumatic Diseases | And 15 more authors.
Journal of Immunotherapy

Wilms tumor gene 1 (WT1) is overexpressed in various malignant neoplasms, and has been demonstrated as an attractive target for cancer immunotherapy. We previously reported the identification of a WT1 protein-derived, 16-mer helper peptide WT1332 that could elicit Th1-type CD4 T-cell response and bind to multiple HLA class II molecules. In this study, we examined the feasibility of adoptive therapy using CD4 T cells that were transduced an HLA-DPB1*05:01- restricted, WT1332-specific T-cell receptor (TCR). HLA-DPB1*05:01- restricted, WT1332-specific TCR-transduced CD4 T cells were successfully generated using lentiviral vector and exhibited strong proliferative response and Th1-type cytokine production in response to WT1332 peptide, WT1 protein, or WT1-expressing tumor cell lysate. Furthermore, the WT1332-specific TCR-transduced CD4 T cells lysed HLA-DPB1*05:01-positive, WT1-expressing human leukemia cells through granzyme B/perforin pathway. Furthermore, stimulation of peripheral blood mononuclear cells with both HLA-A*24:02- restricted cytotoxic T lymphocytes-epitope peptide (modified 9-mer WT1235 peptide, WT1235m) and WT1332 helper peptide in the presence of WT1332-specific TCR-transduced CD4 T cells strikingly enhanced the induction of WT1235m-specific cytotoxic T lymphocytes. Thus, these results demonstrated the feasibility of immunotherapy based on adoptive transfer of WT1332-specific TCR-transduced CD4 T cells for the treatment of leukemia. Copyright © 2013 by Lippincott Williams & Wilkins. Source

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