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

Fusion proteins constructed of a tumor-specific Ab joined to IL-2 (Ab-IL-2) have been used in the past to deliver cytokine directly to the site of tumor cells in vivo. These molecules mimic the activity of IL-2 and assist in activating and expanding antitumor effector cells. To enhance the cytolytic activity of CTL specific for peptide epitopes of the Her-2/neu tumor Ag presented by HLA-A*0201 molecules, a fusion protein was constructed consisting of a single chain Ab specific for Her-2/neu, linked to IL-2 (neu-Ab-IL-2). When added to a mixture of tumor cells and Her-2/neu-specific CTL, the protein was found to augment lysis of tumor cells. In addition, the hybrid molecule also promoted lysis of Her-2/neu expressing tumors by non-tumor-specific cloned T cell lines, including Th1 CD4 cells. Analysis of the mechanism of cytotoxicity revealed that the fusion protein mediates the formation of stable conjugates between T cells expressing IL-2R and tumor cells expressing Her-2/neu, resulting in lysis through the Fas-Fas ligand pathway. Lysis induction was independent of specific engagement by the TCR. When tested for its ability to enhance tumor cell eradication by Her-2/neu-specific CD8+ T cells in an adoptive transfer model in SCID mice, neu-Ab-IL-2 facilitated the elimination of tumor cells in vivo. Surprisingly, the combination of non-tumor-specific CD8+ T cells and fusion protein also induced a significant delay of tumor growth. This represents a novel approach for redirecting non-tumor-specific T cells to eliminate tumors.
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PMID:Redirecting effector T cells through their IL-2 receptors. 988 7

BALB/c mice transgenic (Tg) for the transforming rat neu oncogene (BALB-neuT) are genetically predestined to develop mammary carcinogenesis in a process similar to that in humans. We crossed HLA-A2.1/HLA-DR1 (A2.1/DR1) Tg mice with BALB-neuT mice to generate A2.1/DR1 x BALB-neuT triple Tg (A2.1/DR1 x neuT(+)) mice, which represent an improvement over BALB-neuT mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. A vaccine formulation strategy, consisting of synthetic peptides from the rat HER-2/neu oncogene combined with granulocyte macrophage colony-stimulating factor, was highly effective in preventing the growth of established transplantable tumors in male A2.1/DR1 x neuT(+) mice. Vaccination with HER-2(435-443) (p435) CTL peptide alone induced weak antitumor responses, which were characterized by increased numbers of regulatory T cells (Treg) and low numbers of vaccine-specific CD8(+) CTL and helper T cells (Th). The administration of p435 plus HER-2(776-790) (p776; helper peptide) reversed this situation, inducing functionally active, peptide-specific CTL and Th. There was a striking change in the intratumoral balance of Tregs (decrease) and vaccine-specific Th (increase) that directly correlated with tumor rejection. Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas(+)) was due to apoptosis induced by cell contact with Fas ligand(+) (L)(+) Th. Mice vaccinated with p435 plus p776 exhibited long-lasting antitumor immunity. Our vaccine regimen also significantly delayed the outgrowth of mammary carcinomas in female A2.1/DR1 x neuT(+) animals. We provide a mechanism to overcome tolerance against HER-2/neu, which proposes a combined vaccination with two (Th and CTL) HER-2 peptides against HER-2/neu-expressing tumors.
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PMID:Peptide vaccination breaks tolerance to HER-2/neu by generating vaccine-specific FasL(+) CD4(+) T cells: first evidence for intratumor apoptotic regulatory T cells. 2023 67