Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prevention of the progression of precancerous lesions by vaccines is virtually uncharted territory. Their potential, however, is being assessed in transgenic mice which develop autochthonous tumors with defined stages of progression. In this paper we show that the DNA micro-array technology significantly helps assessment of the preventive efficacy of a combined DNA and cell vaccine. All female rat Her-2/neu transgenic BALB/c (BALB-neuT) mice develop an invasive carcinoma in each of their mammary glands within 25 weeks of age. This is elicited by the activated transforming rat Her-2/neu oncogene embedded in their genome. We have previously shown that vaccination of mice bearing multiple in situ carcinomas with DNA plasmids which code for the extracellular and transmembrane domain of rat p185neu, the product of the rat Her-2/neu oncogene, followed by a boost with rat p185neu+ allogeneic cells engineered to secrete interferon-gamma, keeps 48% of mice tumor free until week 32. We have now extended our follow-up until mice reach one year of age and show that protection vanishes as time progresses. This observation suggests that the accuracy of the results studying immunotherapy against life-threatening tumors is a function of the length of the follow-up. The application of microarrays, and the concordance of morphologic and gene expression data led us to identify antibody as the main mechanism induced by vaccination. Protection is associated with a break of tolerance and a limited autoimmunity against the endogenous mouse p185neu.
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PMID:A limited autoimmunity to p185neu elicited by DNA and allogeneic cell vaccine hampers the progression of preneoplastic lesions in HER-2/NEU transgenic mice. 1588 57

Her-2/neu is a tumor-associated antigen that has been targeted with both antibodies and cytotoxic T lymphocytes (CTL). Despite the isolation of Her-2/neu-reactive CTL in vaccinated patients, their therapeutic use has been limited by the observation that they often do not robustly recognize Her-2/neu(+) tumors. We sought to determine the mechanism for this escape using Ag201P and Ag201M cells, which are murine osteosarcoma tumor lines that express a functional HLA-A2/K(b) molecule. We now demonstrate that Ag201P and Ag201M express low levels of murine Her-2/neu, and that Ag201M was modestly and inconsistently recognized by an HLA-A2-restricted, Her-2/neu-reactive human CTL clone. In order to determine whether inefficient antigen processing might account for the weak recognition, COS-A2 cells were transfected with a short Her-2/neu minigene coding for the immunodominant Her-2/neu:369 epitope that did not require antigen processing or a long Her-2/neu minigene that did require antigen processing. Her-2/neu-reactive CTL clones only recognized COS-A2 cells transfected with the short minigene, indicating that lack of proper antigen processing could be responsible for the poor recognition of target cells. To confirm these results, it was demonstrated that following treatment with interferon-gamma, both Ag201P and Ag201M robustly and consistently stimulated the CTL clones. Furthermore, CTL clone recognition was enhanced following interferon-gamma treatment using another murine tumor line that expressed low levels of Her-2/neu (B16-A2/K(b)). The enhanced recognition of Ag201P and Ag201M in the presence of interferon-gamma was not due to an upregulation of Her-2/neu protein expression. Collectively, these results suggest that inefficient antigen processing of Her-2/neu can contribute to the lack of tumor recognition by CTL. These results also suggest that even tissues that express low levels of Her-2/neu might become CTL targets under conditions in which antigen processing is enhanced.
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PMID:Interferon-gamma renders tumors that express low levels of Her-2/neu sensitive to cytotoxic T cells. 1615 8

Tumour-derived chaperone-rich cell lysate (CRCL), which is made up of numerous heat shock proteins, has been used successfully to generate tumour-specific T cell responses and protective immunity against a wide range of murine tumours. In this study, we have investigated the potency of human ovarian cancer-derived CRCL to activate dendritic cells (DC) and to generate tumour-specific T cells in vitro. CRCL was generated from primary ovarian cancers and SKOV3-A2, a HER2/neu, Wilm's tumour gene 1 (WT1) and human leucocyte antigen (HLA)-A2 positive human ovarian tumour cell line. Peripheral blood mononuclear cells from both HLA-A2(+) healthy donors and HLA-A2(+) ovarian cancer patients were stimulated weekly with autologous DC loaded with ovarian tumour-derived CRCL. After four to six stimulations in vitro, specific cytokine secretion and cytotoxicity were measured. CRCL promoted interleukin (IL)-12 secretion and enhanced the immunostimulatory capacity of DC. T cells from healthy controls and from ovarian cancer patients secreted higher amounts of interferon-gamma following in vitro restimulation with ovarian cancer-derived CRCL than with HER2/neu or WT1 peptide-pulsed DC. We were also able to generate cytotoxic T lymphocyte activity against cancer-specific antigens such as HER2/neu and WT1 from all healthy donors, but from only one of the four ovarian cancer patients with bulky disease. These preliminary results substantiate further the concept that CRCL may prove to be a potent adjuvant for women suffering from ovarian cancer and that this personalized vaccine may be a promising approach for active immunotherapy.
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PMID:Human ovarian tumour-derived chaperone-rich cell lysate (CRCL) elicits T cell responses in vitro. 1734 14

DNA vaccine and dendritic cells (DCs)-based vaccine have emerged as promising strategies for cancer immunotherapy. Fms-like tyrosine kinase 3-ligand (Flt3L) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) have been exploited for the expansion of DC. It was reported previously that combination of plasmid encoding GM-CSF with HER2/neu DNA vaccine induced predominantly CD4(+) T-cell-mediated antitumor immune response. In this study, we investigated the modulation of immune responses by murine Flt3L and GM-CSF, which acted as genetic adjuvants in the forms of bicistronic (pFLAG) and monocistronic (pFL and pGM) plasmids for HER2/neu DNA vaccine (pN-neu). Coexpression of Flt3L and GM-CSF significantly enhanced maturation and antigen-presentation abilities of splenic DC. Increased numbers of infiltrating DC at the immunization site, higher interferon-gamma production, and enhanced cytolytic activities by splenocytes were prominent in mice vaccinated with pN-neu in conjunction with pFLAG. Importantly, a potent CD8(+) T-cell-mediated antitumor immunity against bladder tumors naturally overexpressing HER2/neu was induced in the vaccinated mice. Collectively, our results indicate that murine Flt3L and GM-CSF genes coexpressed by a bicistronic plasmid modulate the class of immune responses and may be superior to those codelivered by two separate monocistronic plasmids as the genetic adjuvants for HER2/neu DNA vaccine.
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PMID:Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine. 1770 54

This review addresses genes differentially expressed in the mammary gland transcriptome during the progression of mammary carcinogenesis in BALB/c mice that are transgenic for the rat neu (ERBB2, or HER-2/neu) oncogene (BALB-neuT664V-E mice). The Ingenuity knowledge database was used to characterize four functional association networks whose hub genes are directly linked to inflammation (specifically, the genes encoding IL-1beta, tumour necrosis factor, interferon-gamma, and monocyte chemoattractant protein-1/CC chemokine ligand-2) and are increasingly expressed during such progression. In silico meta-analysis in a human breast cancer dataset suggests that proinflammatory activation in the mammary glands of these mice reflects a general pattern of human breast cancer.
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PMID:Inflammation and breast cancer. Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice. 1770 81

Developing a process to generate dendritic cells (DCs) applicable for multicenter trials would facilitate cancer vaccine development. Moreover, targeting multiple antigens with such a vaccine strategy could enhance the efficacy of such a treatment approach. We performed a phase 1/2 clinical trial administering a DC-based vaccine targeting multiple tumor-associated antigens to patients with advanced colorectal cancer (CRC). A qualified manufacturing process was used to generate DC from blood monocytes using granulocyte macrophage colony-stimulating factor and IL-13, and matured for 6 hours with Klebsiella-derived cell wall fraction and interferon-gamma (IFN-gamma). DCs were also loaded with 6 HLA-A*0201 binding peptides derived from carcinoembryonic antigen (CEA), MAGE, and HER2/neu, as well as keyhole limpet hemocyanin protein and pan-DR epitope peptide. Four planned doses of 35x10(6) cells were administered intradermally every 3 weeks. Immune response was assessed by IFN-gamma enzyme-linked immunosorbent spot (ELISPOT). Matured DC possessed an activated phenotype and could prime T cells in vitro. In the trial, 21 HLA-A2+ patients were apheresed, 13 were treated with the vaccine, and 11 patients were evaluable. No significant treatment-related toxicity was reported. T-cell responses to a CEA-derived peptide were detected by ELISPOT in 3 patients. T cells induced to CEA possessed high avidity T-cell receptors. ELISPOT after in vitro restimulation detected responses to multiple peptides in 2 patients. All patients showed progressive disease. This pilot study in advanced CRC patients demonstrates DC-generated granulocyte macrophage colony-stimulating factor and IL-13 matured with Klebsiella-derived cell wall fraction and IFN-gamma can induce immune responses to multiple tumor-associated antigens in patients with advanced CRC.
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PMID:Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. 1789 68

Her-2/neu is a well-characterized tumor-associated antigen, the overexpression of which in human carcinomas correlates with a poor prognosis. Here, we evaluated Her-2/neu-specific humoral and cellular immune responses in immunized monkeys after immunization with nonreplicating adenovirus (AdHM) expressing the extracellular and transmembrane domain of human Her-2/neu (HM) and/or naked DNA vaccine (pHM-hGM-CSF) expressing human granulocyte-macrophage colony-stimulating factor together with HM. Priming of monkeys with AdHM generated Her-2/neu-specific long-lasting antibody production. Furthermore, these Her-2/neu-specific antibodies produced by AdHM immunization, some of which shared epitope specificity with Herceptin, were able to induce antibody-dependent cellular cytotoxicity against Her-2-expressing target cells. Cellular immune responses were elicited in all monkeys immunized with Her-2/neu-expressing vaccine; interferon-gamma was secreted when these splenocytes were restimulated with Her-2/neu-expressing autologous cells, and immunization with AdHM induced Her-2/neu-specific lymphoproliferative responses. Further, immunization with pHM-hGM-CSF before AdHM immunization noticeably enhanced cytotoxic T-lymphocyte activity. In addition, we observed no abnormalities that would indicate that the genetic vaccines had toxic effects in the immunized monkeys. Thus, we can conclude that our genetic vaccines efficiently elicited Her-2/neu-specific humoral and cellular immune responses without causing severe adverse effects in nonhuman primates and that as such they warrant further clinical investigation.
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PMID:Immunogenicity and safety profiles of genetic vaccines against human Her-2/neu in cynomolgus monkeys. 1848 Aug 47

The current gene transfer technology for single chain (scFv)-based chimeric immune receptor (CIR) has relied on retrovirus and lentivirus vectors which require a long time to obtain sufficient number of transduced cells and stably incorporate into genome. To ameliorate these limitations, we applied RNA electroporation to human peripheral blood lymphocytes (PBLs) activated with anti-CD3 antibody and interleukin-2 (IL-2) for 3 days and assessed that PBL transiently expressing anti-Her-2/neu CIR (CIR-PBL) containing signaling portion of CD28 and CD3zeta could elicit strong cytotoxicity in vitro and antitumor responses in vivo. The CIR-PBL expressed high level of CIR in CD4+, CD8+ and CD56+ cells. Her-2/neu-specific stimulation induced secretion of type-I cytokines including interferon-gamma (IFN-gamma), IL-8 and granulocyte-macrophage colony-stimulating factor, and IFN-gamma secretion was mainly mediated by CD8+ T cells. CIR-PBL specifically killed SKOV3 cell line expressing Her-2/neu. Adoptive transfer of CIR-PBL in SKOV3 xenograft model led to significant inhibition of tumor growth compared with transfer of mock-transduced PBL and showed higher inhibition than those with Herceptin, humanized monoclonal antibody specific for Her-2/neu. These results provided evidence that electroporation of CIR RNA to human PBLs could be used for rapid generation and high number of therapeutic antigen-specific T cells for adoptive immunotherapy.
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PMID:Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model. 1909 47

Interleukin-12 (IL-12), despite exerting antitumor activity, has limited therapeutic uses due to its systemic toxicity. Since HER2 (also known as ErbB-2, neu, and HER2/neu) is frequently overexpressed on cancer cells, HER2-targeted delivery of IL-12 to tumors may be a promising strategy for enhancing antitumor immunity. Here we showed that intramuscular electrogene transfer of an expression vector encoding a fusion protein antiHER2scFv-IL12, which consists of antiHER2 single-chain variable fragment (scFv) and single-chain IL-12, significantly retarded tumor growth and prolonged the survival in a syngeneic bladder tumor model. Elevated IL-12 and interferon-gamma (IFN-gamma) levels, increased infiltration of CD4(+) and CD8(+) T cells, and reduced vascular endothelial growth factor (VEGF) expression in the tumors, as well as enhanced cytolytic activity of splenocytes were noted in the treated mice. Our results suggest that this approach may be effective for the treatment of HER2-overexpressing tumors.
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PMID:Enhancement of antitumor immune response by targeted interleukin-12 electrogene transfer through antiHER2 single-chain antibody in a murine bladder tumor model. 1959 13


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