Human T cells expressing γδ T cell receptor have a potential to show antigen-presenting cell-like phenotype and function upon their activation. However, the mechanisms that underlie the alterations in human γδ T cells remain largely unclear. In this study, we have investigated the molecular characteristics of human γδ T cells related to their acquisition of antigen-presenting capacity in comparison with activated αβ T cells.
View Article and Find Full Text PDFDendritic cell (DC) vaccine is a promising immunotherapy for cancer due to its ability to induce antigen-specific CTLs efficiently. However, a number of clinical studies have implied insufficient therapeutic benefits with the use of MHC class 1 restricted peptide-pulsed DC vaccine. To enhance the clinical efficacy, we examined combination therapy of DC vaccine pulsed with OVA peptide and intravenous low dose unmodified IL-2 (IL-2 solution) administration against EG7 tumor-bearing mice.
View Article and Find Full Text PDFSpecific cellular immunotherapy for cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that recognize tumor-associated antigens. However, it is difficult to isolate and expand functionally active T-cells ex vivo. In this study, we investigated the efficacy of a new method to induce expansion of antigen-specific CTLs for adoptive immunotherapy.
View Article and Find Full Text PDFTo understand global effector mechanisms of CTL therapy, we performed microarray gene expression analysis in a murine model using pmel-1 T-cell receptor (TCR) transgenic T cells as effectors and B16 melanoma cells as targets. In addition to upregulation of genes related to antigen presentation and the MHC class I pathway, and cytotoxic effector molecules, cell-cycle-promoting genes were downregulated in the tumor on days 3 and 5 after CTL transfer. To investigate the impact of CTL therapy on the cell cycle of tumor cells in situ, we generated B16 cells expressing a fluorescent ubiquitination-based cell-cycle indicator (B16-fucci) and performed CTL therapy in mice bearing B16-fucci tumors.
View Article and Find Full Text PDFSeveral types of immune-cell therapies, such as αβ T-cell, γδ T-cell, and dendritic cell (DC) vaccine therapies, are clinically employed for cancer treatment. The safety of immune-cell therapy for the treatment of patients with malignancies should be maintained by continuous assessment of adverse events. In the present study, we surveyed the adverse events associated with immune-cell therapy using large-scale prospective data and analyzed the side-effect profiles.
View Article and Find Full Text PDFThe addition of zoledronate to tumor-associated antigen (TAA)-loaded dendritic cells (DCs) promotes the activation of interferon γ-secreting Vγ9 γδ T cells, in turn eliciting TAA-specific CD8 T-cell responses. Immunological responses induced by zoledronate-pulsed DC-based vaccines have been associated with therapeutic effects in clinical trials.
View Article and Find Full Text PDFRecent progress has been made in understanding the mechanisms of antitumor immune responses, which may further clarify the immune status of cancer patients. In this study, we performed a detailed evaluation of the immunological status of 47 patients with advanced solid cancer, who had received no immunosuppressive treatment, and compared the results with 32 healthy subjects. Flow-cytometry data for peripheral blood were obtained using 19 monoclonal antibodies against various cell surface and intracellular molecules.
View Article and Find Full Text PDFComplex interactions among multiple cell types contribute to the immunosuppressive milieu of the tumor microenvironment. Using a murine model of adoptive T-cell immunotherapy (ACT) for B16 melanoma, we investigated the impact of tumor infiltrating cells on this complex regulatory network in the tumor. Transgenic pmel-1-specific cytotoxic T lymphocytes (CTLs) were injected intravenously into tumor-bearing mice and could be detected in the tumor as early as on day 1, peaking on day 3.
View Article and Find Full Text PDFDendritic cell (DC)-based vaccines with the use of various antigen loading methods have been developed for cancer immunotherapy. Electroporation (EP) of a whole tumor cell lysate into DCs was previously found to be more potent for eliciting antigen-specific CD8 + T-cells compared to co-incubation of tumor cell lysates with DCs in vitro. In the present report, we studied the feasibility, safety and antitumor effect in the clinical use of an EP-DC vaccine for the immunotherapy of various types of human solid tumors.
View Article and Find Full Text PDFRecent commercial approval of cancer vaccine, demonstrating statistically significant improvement in overall survival of prostate cancer patients has spurred renewed interest in active immunotherapies; specifically, strategies that lead to enhanced biological activity and robust efficacy for dendritic cell vaccines. A simple, widely used approach to generating multivalent cancer vaccines is to load tumor whole cell lysates into dendritic cells (DCs). Current DC vaccine manufacturing processes require co-incubation of tumor lysate antigens with immature DCs and their subsequent maturation.
View Article and Find Full Text PDFTargeting dendritic cells in vivo by transcutaneous peptide immunization (TCI) represents an efficient immunization strategy to induce tumor-specific CTL because it reflects the physiologic conditions occurring during pathogen infection. Here we show that including a Th1 peptide in TCI can activate preexisting memory Th1 (mTh1) responses and thereby enhance the CTL response. For this purpose, peptide-25, a major Th1 epitope of Ag85B from Mycobacterium tuberculosis, was selected.
View Article and Find Full Text PDFBiochem Biophys Res Commun
June 2008
Dendritic cells (DCs) transfected with mRNA encoding tumor-associated antigens (TAAs) can induce tumor-specific T-cell responses. To potentiate this, we transfected mature DCs (mDCs) with mRNA encoding TAA targeted to the proteasome. DCs were generated from bone marrow cells by culture with 20 ng/ml GM-CSF and maturation with 1 microg/ml LPS.
View Article and Find Full Text PDFTwo analogues possessing steric hindered substituents on C-15 of arenastatin A (1), a potent cytotoxic spongean depsipeptide, were synthesized and shown to enhance stability in mouse serum. Notably, 15-tert-butylanalogue (6) with higher cytotoxicity exhibited in vivo anti-tumor activity through iv administration different from 1. Additionally, conformation analysis among the two analogues and arenastatin A (1) indicated that the torsion angle from C-14 to C-20 is a conclusive factor for the potent cytotoxicity of 1.
View Article and Find Full Text PDFAlpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix, while beta-dystroglycan is a type I integral membrane protein which anchors alpha-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of alpha- and beta-dystroglycan is called the dystroglycan complex. Although defects of the dystroglycan gene have not been identified as the primary causes of hereditary diseases in humans, secondary but significant abnormalities of the dystroglycan complex have been revealed in severe muscular dystrophies, including sarcoglycanopathy (LGMD2C, D, E and F).
View Article and Find Full Text PDFBackground: MMI-166 is a selective matrix metalloproteinase (MMP) inhibitor. The purpose of this study was to evaluate the antitumor efficacy of the combined treatment of MMI-166 with paclitaxel or carboplatin.
Materials And Methods: Mice bearing B16-BL6 melanoma were treated p.
Gan To Kagaku Ryoho
November 2002
The antitumor activity of a combination of paclitaxel (TXL) followed by nedaplatin (NDP) against SK-OV-3 human ovarian cancer was evaluated. We also compared the antitumor activity of TXL plus NDP with that of TXL plus carboplatin (CBDCA) or TXL plus cisplatin (CDDP). TXL was injected i.
View Article and Find Full Text PDFThe anti-metastatic efficacy of MMI-166, which is a selective matrix metalloproteinase (MMP) inhibitor, in combination with CPT-11 was examined using two metastasis models of human gastrointestinal cancer cells. In the liver metastasis model, C-IH human colon cancer cells were injected into the spleen of athymic BALB/c nude mice. Daily oral (p.
View Article and Find Full Text PDFRecombinant interleukin-2 (IL-2) was strongly and almost completely adsorbed onto small hydrophobic liposomes under optimal conditions (liposome: DSPC-DSPG; molar ratio, 10:1; 30-50 nm in size, ratio of IL-2 to liposome: 4.0 JRU/nmol lipid). This liposomal IL-2 improved the distribution of IL-2 after intravenous administration as reported, previously.
View Article and Find Full Text PDFThe antitumor efficacy of the combination of nedaplatin (NDP) with gemcitabine (GEM) was evaluated against Ma44/GEM, a GEM-refractory subline of Ma44 human lung cancer, which was established by serial in vitro passage of Ma44 cells in the presence of GEM.Ma44/GEM showed less sensitivity to GEM and cytosine arabinoside with resistance factors of 7.7 and 8.
View Article and Find Full Text PDFMatrix metalloproteinases (MMPs) have been reported to be involved in various inflammatory disorders. Previous studies revealed that MMP-2 and MMP-9 might play important roles in the breakdown of the blood-brain barrier (BBB) in the central nervous system (CNS) of patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). N-Biphenyl sulfonyl-phenylalanine hydroxamic acid (BPHA) selectively inhibits MMP-2, -9 and -14, but not MMP-1, -3 and -7.
View Article and Find Full Text PDFObjectives: The aim of our study was to evaluate the anti-invasive effect of MMI-166, a new matrix metalloproteinase (MMP) inhibitor in cervical carcinoma cell lines.
Methods: We analyzed the invasive activities of cervical carcinoma cell lines (CAC-1, CaSki, and SiHa) and the gene expression of various matrix proteinases (matrix metalloproteinase-1 [MMP-1], MMP-2, MMP-9, membrane-type MMP type 1 [MT1-MMP], MT2-MMP, and MT3-MMP) and their inhibitors (tissue inhibitor of metalloproteinase type 1 [TIMP-1] and TIMP-2). The effect of MMI-166 was analyzed by in vitro invasion assay.
Matrix metalloproteinases (MMPs) have been implicated in tumor invasion, metastasis, and angiogenesis. We have recently shown that MMI-166, a new orally active MMP inhibitor specific for MMP-2 and -9, suppressed experimental metastasis of Lewis lung cancer, C-H1 human colon cancer, and pancreatic cancer without affecting tumor growth in vitro. In the present study, we determined whether oral administration of MMI-166 reduces tumor growth not only in such tumors but also in squamous cell carcinoma of head and neck (SCCHN).
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