UNIPROT:P04626 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.
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PMID:Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. 933 60

A chimeric receptor, consisting of the single-chain variable (scFv) domains of an anti-erbB-2 mAb linked via a CD8 membrane-proximal hinge to the Fc receptor gamma chain, was expressed in the mouse cytotoxic T lymphocyte (CTL) hybridoma cell line, MD45. This cell line was grafted with the additional specificity to recognise and bind erbB-2-expressing breast carcinoma target cells T47D, MCF-7 and BT-20 in a non-MHC-restricted manner. Tumour cell lysis was antigen-specific since erbB-2-negative tumours were insensitive to lysis by MD45-scFv-anti-erbB-2-gamma clones, and lysis of erbB-2+ tumour targets was inhibited in the presence of an anti-erbB-2 mAb. Furthermore, target cell death correlated with the level of chimeric receptor expression on the effector MD45 subclones. Redirected MD45 CTL utilised Fas ligand to induce target cell death since soluble Fas-Fc fusion protein completely inhibited cytolysis. The sensitivity of tumour target cells to Fas ligand was further enhanced by treating them with interferon-gamma, a regulator of Fas and downstream signalling components of the Fas pathway. Overall, this study has demonstrated the requirement for successful activation of Fas ligand function in conjunction with cytokine treatment for effective lysis of breast carcinoma target cells mediated by redirected CTL.
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PMID:Fas-ligand-mediated lysis of erbB-2-expressing tumour cells by redirected cytotoxic T lymphocytes. 1002 72

Freshly isolated human polymorphonuclear cells (PMNCs) constitutively express Fcgamma receptor (Fc-gammaR) II and FcgammaRIII on the cell surface but not FcgammaRI. Cytokines such as interferon-gamma (IFNgamma), granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF trigger FcgammaRI expression on (PMNCs). Because PMNCs express interleukin (IL)-2 receptor, we investigated whether IL-2 can induce FcgammaRI expression on PMNCs isolated from IL-2-treated metastatic renal cell carcinoma (MRCC) and low-grade non-Hodgkin lymphoma (LGNHL) patients. Pretherapy flow cytometry analysis of Fcgamma receptors on PMNCs did not show FcgammaRI expression. Interestingly, 3 days after therapy, PMNCs displayed a detectable amount of FcgammaRI on the cell surface. Kinetic studies on the in vivo effects of IL-2 on MRCC patients showed that FcgammaRI was transiently expressed, starting within 3-6 days of therapy, remaining expressed for 10-15 days, and rapidly declining, whereas such expression remained stable for months in LGNHL patients. In contrast, Fc-gammaRII was not affected. In addition, FcgammaRI+ PMNCs coated in vitro with a bispecific antibody Fab anti-FcgammaRI x anti-HER-2/neu formed intercellular conjugates with a human HER-2/neu-transfected 3T3 cell line (HER-2/neu-3T3). Interleukin-2 treatment increased the number of FcgammaRIII low eosinophils, leading to a change in FcgammaRIII distribution among granulocyte cell subsets. In vitro IL-2 treatment of purified PMNCs failed to generate Fc-gammaRI expression, suggesting that IL-2 indirectly causes FcgammaRI expression. During the IL-2 administration, we did not observe significant changes in IFNgamma serum level. In conclusion, our observation may be used to potentiate the antitumor effects of IL-2 in novel immunotherapy regimens, perhaps by redirecting FcgammaRI+ PMNCs against cancer cells by heteroconjugate antibodies and monitoring the biologic activity of subcutaneous IL-2 in cancer patients.
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PMID:Subcutaneous administration of interleukin-2 triggers Fcgamma receptor I expression on human peripheral blood neutrophils in solid and hematologic malignancies. 1156 39

Dendritic cells (DCs) are potent antigen-presenting cells and have shown promise to function as "natural" vaccine adjuvants. Currently, most cancer vaccine trials using DCs generate autologous DCs ex vivo for each patient. Systemic treatment with Flt3 ligand (FL) results in a marked increase of DCs in tissues such as spleen and lymph nodes in mice and in the peripheral blood and skin of humans. In light of these observations, we questioned whether FL could be used systemically as a vaccine adjuvant to stimulate DC mobilization in vivo, circumventing the need to generate DCs ex vivo. Ten patients with HER-2/neu-overexpressing cancer were enrolled in a phase 1 study to receive a HER-2/neu peptide-based vaccine targeting the intracellular domain of the HER-2/neu protein. All patients received 20 microg/kg FL per day subcutaneously for 14 days. Five patients received the HER-2/neu peptide-based vaccine alone on day 7 of the 14-day cycle, and 5 patients received the vaccine admixed with 150 microg granulocyte macrophage-colony-stimulating factor (GM-CSF) on day 7 of the FL cycle. T-cell proliferative responses to HER-2/neu peptides and intracellular domain protein suggest that vaccine regimens including FL as an adjuvant were not effective in eliciting a significant HER-2/neu protein-specific T-cell proliferative response. However, including FL as a vaccine adjuvant was effective in boosting the precursor frequency of interferon-gamma-secreting HER-2/neu-specific T cells. The small sample size of each group, however, did not allow a statistically significant comparison of immune responses between the FL alone and FL with GM-CSF arms. Finally, vaccine regimens including FL as a vaccine adjuvant were associated with the development of apparent autoimmune phenomena in some patients.
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PMID:Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu-overexpressing cancers. 1192 74

HER-2/neu peptides have recently been shown to induce a proliferative response by peripheral CD4(+) T cells in breast cancer patients. To investigate potential differences in the local cellular immune response between breast cancer patients with and without nodal metastases, lymphocytes were isolated from axillary lymph nodes from patients with breast cancer, and proliferative and cytokine responses to HER-2/neu peptides were determined. Freshly isolated lymphocytes from lymph nodes of 7 women undergoing surgery for invasive breast cancer were plated at 20 x 10(5) cells per well in triplicate. Cells were stimulated with HER-2/neu peptides at 50 microg/ml and with control antigens. Incorporation of tritium-labeled thymidine was determined 4 days later. The levels of the cytokines interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and IL-10 were determined at priming and at restimulation with HER-2/neu peptides using a cytokine-specific, double-sandwich, enzyme-linked immunosorbent assay (ELISA). Lymphocytes isolated from the axillary lymph nodes of the patients mounted significant cellular immune response to HER-2/neu peptides, manifested by proliferation and specific cytokine elaboration. Proliferative responses to HER-2/neu peptides were seen in lymphocytes of patients with and without overexpression of HER-2/neu in the primary tumor. In some patients, the proliferative response to HER-2/neu peptides in lymphocytes from lymph nodes with metastases was absent or blunted compared with the response in lymphocytes from lymph nodes without metastases from the same patient (p < 0.05). HER-2/neu peptides induced a predominantly T helper type 1 (Th1) pattern of cytokine response in nodal lymphocytes isolated from breast cancer patients. A Th1-specific cytokine production pattern was maintained at priming and restimulation with HER-2/neu peptides and was amplified with IL-12 costimulation. These results indicate that HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. This activation is associated with a predominantly Th1 cytokine response, which suggests that conditioning with HER-2/neu peptides may be of value in the development of breast cancer vaccines.
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PMID:Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast. 1206 Apr 97

Natural antigen processing and presentation of antigen is thought to be important for the generation of a broad functional repertoire of antigen-specific T cells. In this study, the T-cell repertoire to an immunodominant human leukocyte antigen A2 (HLA-A2) binding peptide epitope of HER-2/neu, p369-377, was examined in a patient following immunization with a peptide-based vaccine consisting of helper peptides encompassing HLA-A2 peptide epitopes. The responding T-cell repertoire generated was both phenotypically and functionally diverse. A total of 21 p369-377 clones were generated from this patient. With the exception of two clones, all clones were CD3(+). Sixteen of the clones were CD8(+)/CD4(-). Five of the clones were CD4(+)/CD8(-), despite being generated with an HLA-A2 binding peptide. Nineteen of 21 of clones expressed the alpha beta-T-cell receptor (TCR). The remaining two clones expressed the gamma delta T-cell response (TCR). Selected alpha beta-TCR clones, both CD8(+) and CD4(+), could lyse HLA-A2 transfected HER2 overexpressing tumor cells and p369-377-loaded B-lymphoblastic cell line. In addition to their lytic capabilities these clones could be induced to produce interferon-gamma (IFN-gamma) specifically in response to p369-377 peptide stimulation. The 2 gamma delta-TCR clones expressed CD8 and lysed HLA-A2(+) HER-2/neu(+) tumor cells, but not HLA-A2(-) HER-2/neu(+) tumor cells. One of gamma delta-TCR clones also released IFN-gamma directly in response to p369-377 stimulation. These results suggest that a tumor antigen TCR, directed against a specific epitope, can be markedly polyclonal at multiple levels including CD4/CD8 and TCR.
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PMID:Clonal diversity of the T-cell population responding to a dominant HLA-A2 epitope of HER-2/neu after active immunization in an ovarian cancer patient. 1207 90

A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using flt3 ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 ligand (20 microg/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) flt3 ligand course as above with the E75 peptide vaccine administered on day 7 of each flt3 ligand cycle; (c) flt3 ligand course as above with the E75 peptide vaccine administered on day 14 of each flt3 ligand cycle; or (d) E75 peptide admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot. Adverse events included one grade 3 skin reaction and the development of grade 2 autoimmune hypothyroidism in two subjects with preexisting subclinical autoimmune hypothyroidism. Dendritic cells were markedly increased in the peripheral blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. Apart from a single subject, no significant peptide-specific T-cell responses were detected by ELIspot, whereas delayed-type hypersensitivity responses were detectable in control subjects and in subjects receiving peptide vaccine early in the course of flt3 ligand administration. The absence of robust peripheral immune responses in the current study may be attributable to the small numbers of subjects or differences in the subject population. In addition, the inability of fit3 ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptide-specific immunity detectable in the peripheral blood of immunized subjects treated with flt3 ligand.
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PMID:Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant. 1264 61

FVB-NeuN (N#202) female mice transgenic for the HER-2/neu protooncogene driven by the murine mammary tumor virus (MMTV) promoter develop mammary carcinomas with a progression from focal atypical hyperplasia to in situ carcinoma and to invasive carcinoma that closely resembles that of human neoplasia. Here we report that the combination of tamoxifen plus interleukin 12 (IL-12) results in a very effective prevention of mammary carcinogenesis, significantly higher than those obtained with either tamoxifen or IL-12 alone. At 1 year of age, 20% of control mice resulted tumor-free, whereas 80% of mice receiving the combined treatment were tumor-free. At 2 years of age, less than 5% of control mice were tumor-free, as opposed to 70% of mice treated with tamoxifen plus IL-12. The combined treatment inhibited mammary carcinogenesis mainly through a reduction in the number of mammary cells at risk of progression, a reduction in estrogen receptors (ERs) expression and a reduction in the angiogenic support to mammary development, likely due to cross-talk between tamoxifen and interferon-gamma (IFN-gamma) (the main downstream mediator elicited in vivo by IL-12). The addition of IL-12 to the tamoxifen treatment more than doubled mouse lifetime and did not exacerbate known side effects of tamoxifen.
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PMID:Prevention of HER-2/neu transgenic mammary carcinoma by tamoxifen plus interleukin 12. 1270 73

Adjuvant treatment is still only working in a small percentage of breast cancer patients. Therefore, new strategies need to be developed. Immunotherapies are a very promising approach because they could successfully attack tumor cells in the stage of dormancy. To assess the feasibility of using an allogeneic approach for vaccination of breast cancer patients, we selected a CD80-transfected breast cancer cell line based on its immunogenic properties. Using CD80+ KS breast cancer cells and human leukocyte antigen (HLA)-A*02-matched peripheral blood mononuclear cells (PBMCs) of breast cancer patients in allogeneic mixed lymphocyte-tumor cell cultures (MLTCs), it was possible to isolate HLA-A*02-restricted cytotoxic T cells (CTLs). Furthermore, a genetically modified KS variant expressing influenza A matrix protein serving as a surrogate tumor-associated antigen (TAA) was able to stimulate flu peptide-specific T cells alongside the induction of alloresponses in MLTCs. KS breast cancer cells were demonstrated to express already known TAAs such as CEA, MUC-1, MAGE-1, MAGE-2, and MAGE-3. To further improve antigenicity, HER-2/neu was added to this panel as a marker antigen known to elicit HLA-A*02-restricted CTLs in patients with breast cancer. Thus, the antigen-processing and antigen-presentation capacity of KS cells was further demonstrated by the stimulation of HER-2/neu-specific CD8+ T cells in PBMCs of breast cancer patients in vitro. These results gave a good rationale for a phase I/II trial, where the CD80+ HER-2/neu-overexpressing KS variant is actually used as a cellular vaccine in patients with metastatic breast cancer. As a proof of principle, we present data from two patients where a significant increase of interferon-gamma (IFN-gamma) release was detected when postvaccination PBMCs were stimulated by allogeneic vaccine cells as well as by HLA-A*02-restricted HER-2/neu epitopes. In whole cell vaccine trials, monitoring is particularly challenging because of strong alloresponses and limited knowledge of TAAs. In this study, a panel of HER-2/neu epitopes, together with the quantitative real time (qRT)-PCR method to analyze vaccine-induced cytokines secreted by T cells, proved to be highly sensitive and feasible to perform an "immunological staging" following vaccination.
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PMID:A CD80-transfected human breast cancer cell variant induces HER-2/neu-specific T cells in HLA-A*02-matched situations in vitro as well as in vivo. 1536 76

Cancer vaccines designed to elicit an antibody response that target antigenic sites on a tumor antigen must closely mimic the three-dimensional structure of the corresponding region on the antigen. We have designed a complex immunogen derived from the extracellular domain of human HER-2/neu-(626-649) that represents a three-dimensional epitope. We have successfully introduced two disulfide bonds into this sequence, thereby recapitulating the natural disulfide pairings observed in the native protein. To evaluate the immunogenicity of the doubly cyclized disulfide-linked peptide versus the free uncyclized peptide we examined the induction of antibody responses in both inbred and outbred mice strains, with both constructs eliciting high titered antibodies. The disulfide-paired specific antibodies exhibited enhanced cross-reactivity to HER-2/neu expressed on BT-474 cell line as determined by flow cytometry. The antitumor activities of the disulfidepaired specific antibodies did not improve the in vitro growth inhibition of human breast cancer cells overexpressing HER-2, but showed superior antitumor responses in the context of ADCC and interferon-gamma induction. Inbred mice (FVB/n) vaccinated with the disulfide-paired epitope exhibited a statistically significant reduction in the development of exogenously administered tumors in vivo compared with mice receiving either the free uncyclized or the promiscuous T-cell epitope (MVF) control peptide (p = 0.001). This study demonstrates the feasibility and importance of designing conformational epitopes that mimic the tertiary structure of the native protein for eliciting biologically relevant anti-tumor antibodies. Such approaches are a prerequisite to the design of effective peptide vaccines.
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PMID:Conformational HER-2/neu B-cell epitope peptide vaccine designed to incorporate two native disulfide bonds enhances tumor cell binding and antitumor activities. 1550 52

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