Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cells genetically modified to secrete immunoregulatory cytokines offer great promise for human cancer treatment as tumor vaccines. However, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccine therapy tends to cure only animals bearing 1 x 10(5) wild-type CT26 cells or less. For many human cancers, antineoplastic chemotherapy can often significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the breast, colon, and prostate, antineoplastic drug treatments generally fail to effect cancer cures. Treatment regimens combining genetically-modified cancer cell vaccine therapy and antineoplastic chemotherapy have the potential to increase advanced cancer cure rates if antineoplastic drugs and drug combinations that do not inhibit vaccine-induced immune responses can be identified. To assess the potential immunomodulatory properties of commonly-used antineoplastic drugs that might be used in combination with cancer vaccine treatments, we studied the effects of the drugs on antitumor immune responses manifest by animals receiving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunomodulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytotoxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculac of CT26 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxorubicin was found to possess apparent immunostimulatory activities, depending on the dose and schedule of administration, while cyclophosphamide appeared immunosuppressive. The different immunomodulatory properties of doxorubicin and cyclophosphamide may be clinically relevant: combination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, while combination cyclophosphamide and vaccine treatment of animals carrying CT26 tumors was no better in curing the animals than drug treatment alone.
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PMID:Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. 945

We explored the potential therapeutic benefit of introducing GM-CSF, IFN-gamma or a combination of both factors into CT26 tumor cells. CT26 cells secreting either GM-CSF or IFN-gamma exhibited delayed tumorigenicity; however, cells expressing both GM-CSF and IFN-gamma did not form tumors. Even when wild type CT26 cells were introduced into a distant site of mice that had been inoculated with CT26/GM-CSF/IFN-gamma cells, no tumors were generated. Furthermore, when we injected GM-CSF + IFN-gamma cells into animals bearing established tumors, the tumors were either rejected or their development was delayed, suggesting that synergistic effects were induced against these tumors via a systemic immune response. Histopathological examination of the tumors injected with cells expressing GM-CSF and IFN-gamma combined showed necrosis and few signs of malignancy. The growth of tumors from mice treated with CT26/GM-CSF/IFN-gamma cells exhibited a delay in tumor formation and no effects were seen in athymic nude mice, which are deficient in T lymphocytes, or in splenectomized nude mice, which are deficient in natural killer (NK) cells, respectively. Our data indicate a dual role for T and NK cells in mediating the anti-tumor activity of this therapy. Our results suggest that transduction of tumor cells with both GM-CSF + IFN-gamma results in a powerful synergistic effect of the 2 cytokines that is of greater therapeutic benefit than transduction with either cytokine alone.
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PMID:Synergistic anti-tumor effects with co-expression of GM-CSF and IFN-gamma in murine tumors. 971 62

The characterization of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer therapy. Several categories of cancer-associated antigens have been described as targets for cytotoxic T lymphocytes (CTLs) in vitro and in vivo: "cancer-testis" (CT) antigens expressed in different tumors and normal testis, melanocyte differentiation antigens, point mutations of normal genes, antigens that are overexpressed in malignant tissues, and viral antigens. Clinical studies using peptides derived from these antigens have been initiated to induce specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e., induction of delayed-type hypersensitivity (DTH), CTL, autoimmune, and tumor regression responses. Preliminary results demonstrate that tumor-associated peptides alone elicit specific DTH and CTL responses leading to tumor regression after intradermal injection. GM-CSF was proved to be effective in enhancing peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Long-lasting complete tumor regressions have been observed after induction of CTLs by peptide immunization. However, in a few cases where there was disease progression after initial tumor response, loss of either the tumor antigen targeted by CTLs or of the presenting MHC class I molecule was detected as the mechanism of immune escape under immunization in vivo. Based on these observations, cytokines to enhance antigen and MHC class I expression in vivo are being evaluated to prevent immunoselection. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1. In a melanoma patient with high titer antibody against NY-ESO-1, strong HLA-A2-restricted CTL reactivity against the same antigen was also found. Clinical studies involving tumor antigens that induce both antibody and CTL responses will show whether these are better candidates for immunotherapy of cancer.
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PMID:Strategies for the development of vaccines to treat breast cancer. 992 50

Anti-idiotype antibody, 11D10 mimics biologically and antigenically a distinct and specific epitope of the high molecular weight human milk fat globule (HMFG), a cancer-associated antigen present in over 90% of breast tumor samples. To augment the immunogenicity of 11D10 without the aid of a carrier protein or adjuvant, we made a chimeric 11D10-GM-CSF fusion protein for use as a vaccine. An expression plasmid for 11D10 was made by ligation of the DNA sequences of the 11D10 light-chain variable region upstream of the human kappa constant region. The heavy-chain plasmid carrying GM-CSF was made by ligation of the heavy-chain variable region sequences upstream of the human gamma1 constant region CH1 fused to the DNA fragment encoding the mature GM-CSF peptide 3' to the CH3 exon. NS1 plasmacytoma cells were transfected with the light and heavy-chain vectors by electroporation. Fusion protein secreted in the culture medium was purified and was characterized by gel electrophoresis as well as by determination of the biological activity of the fused GM-CSF. In nonreducing SDS-polyacrylamide gels, a single band approximately 200 Kd reacted with anti-human kappa, anti-human lambda1 and anti-GM-CSF antibodies. In reducing polyacrylamide gels, a approximately 74 kd protein reacted with anti-human lambda1 and anti-GM-CSF antibodies. The fusion protein induced proliferation of GM-CSF dependent NFS-60 cells. These results suggest that the protein is a chimeric anti-idiotype antibody consisting of 11D10 variable domains, human kappa and lambda1 constant domains and that the GM-CSF moiety fused to the constant region lambda1 is biologically active.
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PMID:Construction and characterization of a chimeric fusion protein consisting of an anti-idiotype antibody mimicking a breast cancer-associated antigen and the cytokine GM-CSF. 1038 19

The characterization of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer therapy. Several categories of cancer-associated antigens have been described as targets for cytotoxic T lymphocytes (CTL) in vitro and in vivo: (1) 'Cancer-Testis' (CT) antigens expressed in different tumors and normal testis, (2) melanocyte differentiation antigens, (3) point mutations of normal genes, (4) antigens that are overexpressed in malignant tissues, and (5) viral antigens. Clinical studies with peptides derived from these antigens have been initiated to induce specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e. induction of DTH-, CTL-, autoimmune-, and tumor-regression responses. Preliminary results demonstrate that tumor-associated peptides alone elicit specific DTH- and CTL-responses leading to tumor regression after intradermal injection. GM-CSF was proven effective to enhance peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Long lasting complete tumor regressions have been observed after induction of CTL by peptide immunization. Based on these results, active immunotherapy with tumor-associated antigens may be a promising approach for patients with minimal residual disease, who are at high risk for tumor recurrence. However, in single cases with disease progression after an initial tumor response either a loss of the respective tumor antigen targeted by CTL or of the presenting MHC class I molecule was detected as mechanisms of immune escape under immunization in vivo. Based on these observations, cytokines to enhance antigen- and MHC-class I expression in vivo are being evaluated to prevent immunoselection. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1. In a melanoma patient with high titer antibody against NY-ESO-1 also a strong HLA-A2 restricted CTL reactivity against the same antigen was found. Clinical studies involving tumor antigens that induce both antibody- and CTL-responses will show whether these are better candidates for immunotherapy of cancer.
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PMID:CTL-defined cancer vaccines: perspectives for active immunotherapeutic interventions in minimal residual disease. 1050 52

Hypereosinophilia may be seen in the blood or tissues of cancer patients. A part of lymphomas, the tumors more frequently involved in such eosinophilia, are digestive and respiratory tract carcinomas. The prevalence of cancer-associated eosinophilia is very variable among the different kind of tumors. These cancer-associated eosinophilia are the results of the secretion by tumor or inflammatory cells of interleukin-3 and -5 and GM-CSF. The anti-cancer properties of eosinophilic polymorphonuclear are poorly understood and the prognostic significance of cancer-associated blood or tissue eosinophilia has not been assessed by controlled studies.
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PMID:[Hypereosinophilic reactions in cancer]. 1080 16

We evaluated the effect of potential therapeutic genes, GM-CSF and IL-2 respectively, or in combination of both cytokines, on the activation of systemic antitumor responses. CT26 tumor cells were modified to secrete GM-CSF and/or IL-2. The growth rate of the modified tumor cells versus the parental CT26 cells did not show any difference. When we implanted the CT26 tumor cells which secrete either GM-CSF or IL-2, delayed and suppressed tumorigenicity was observed. However, another CT26 cell line which expresses both GM-CSF and IL-2 (CT26/GMCSF/IL-2) did not form any tumor mass in the immunocompetent syngeneic Balb/c mice, showing the potential immune responses. Immunohistochemical examination of the modified tumor masses implanted with the cells expressing GM-CSF or IL-2 showed increased necrosis and infiltration of NK (CD56+) lineage cells and macrophage/monocytes. In the vaccination model, the growth of rechallenged wild-type CT26 was more suppressed int he mice which were injected with GM-CSF or IL-2, however, the wild-type CT26 tumor formed normal tumor mass in the mice vaccinated with CT26/GM-CSF/IL-2 showing acute non-T-cell mediated immune response. As a treatment, we injected those modified tumor cells into the established tumor. There we could find tumor growth suppression by the injection of cytokine-modified CT26 cells, especially by the CT26/GM-CSF/IL-2. In the present study we could induce the eradication of tumorigenicity by the transfection of both GM-CSF and IL-2 genes and a potent role in the growth suppression of an established tumor.
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PMID:Effect of GM-CSF and IL-2 co-expression on the anti-tumor immune response. 1095 43

In order to establish a highly metastatic variant of a mouse colon carcinoma cell line (CT26), BALB/c mice were first subcutaneously injected with CT26 cells. Several weeks later, metastatic tumors in lungs were resected, mechanically dispersed into a single cell suspension and cultured in vitro until cells reached confluency. These tumor cells were then subcutaneously injected into new mice. After repeating this procedure five times, a highly lung metastatic cell line, denoted as LM17, has been established. The LM17 cells grow in vitro with or without serum, whereas parental CT26 cells require serum for their growth. The LM17 cells adhere to type I collagen or fibronectin stronger than CT26 cells do. The LM17 cells invade through Matrigel-coated basement membrane in greater number than CT26 cells. By gelatin zymography, LM17 cells showed higher proteinase activity than CT26. Furthermore, subcutaneous injection of irradiated LM17 cells infected with adenovirus harboring mouse GM-CSF gene prevents the growth and lung metastasis of pre-existing subcutaneous tumor. The injection of irradiated GM-CSF-producing LM17 cells after the surgical removal of pre-existing tumor also protected the occurrence of lung metastasis. These results suggest that this highly metastatic LM17 cell line could be useful for analysis of the lung metastatic mechanism and as the mouse GM-CSF gene therapy model.
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PMID:Highly metastatic variant of a mouse colon carcinoma cell line, LM17 and its response to GM-CSF gene therapy. 1108 83

Tumor-associated antigens recognized by cellular or humoral effectors of the immune system represent attractive targets for antigen-specific cancer therapy. Different groups of cancer-associated antigens have been identified inducing cytotoxic T-lymphocyte (CTL) responses in vitro and in vivo: 1) 'Cancer-Testis' (CT) antigens, which are expressed in different tumors and normal testis, 2) melanocyte differentiation antigens, 3) point mutations of normal genes, 4) antigens that are overexpressed in malignant tissues, and 5) viral antigens. Clinical studies with peptides derived from these antigens have been initiated to study the induction of specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i. e., delayed-type hypersensitivity (DTH), CTL, autoimmune, and tumor regression responses. Early results show that tumor-associated peptides alone induce specific DTH and CTL responses and tumor regression after intradermal administration. GM-CSF was used as an adjuvant to enhance peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Complete tumor regressions have been observed in the context of measurable peptide-specific CTL. However, in single cases with disease progression after an initial tumor response, either a loss of the respective tumor antigen targeted by CTL or of the presenting MHC class I allele was detected, suggesting immunization-induced immune escape. Based on these observations, cytokines to modify antigen and MHC class I expression in vivo are being tested to prevent immunoselection. Recently, a new CT antigen, NY-ESO-1, has been identified with a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX). NY-ESO-1 is regarded as one of the most immunogenic antigens known today, inducing spontaneous immune responses in 50% of patients with NY-ESO-1-expressing cancers. Clinical studies with antigenic constructs to induce both humoral and cellular immune responses will show whether these are more effective for immunotherapy of cancer. Copyright 2000 S. Karger GmbH, Freiburg
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PMID:Peptide Vaccination in Clinical Oncology. 1144 Dec 34

Direct intratumor injection of a disabled infectious single cycle HSV-2 virus encoding the murine GM-CSF gene (DISC/mGM-CSF) into established murine colon carcinoma CT26 tumors induced a significant delay in tumor growth and complete tumor regression in up to 70% of animals. Pre-existing immunity to HSV did not reduce the therapeutic efficacy of DISC/mGM-CSF, and, when administered in combination with syngeneic dendritic cells, further decreased tumor growth and increased the incidence of complete tumor regression. Direct intratumor injection of DISC/mGM-CSF also inhibited the growth of CT26 tumor cells implanted on the contralateral flank or seeded into the lungs following i.v. injection of tumor cells (experimental lung metastasis). Proliferation of splenocytes in response to Con A was impaired in progressor and tumor-bearer, but not regressor, mice. A potent tumor-specific CTL response was generated from splenocytes of all mice with regressing, but not progressing tumors following in vitro peptide stimulation; this response was specific for the gp70 AH-1 peptide SPSYVYHQF and correlated with IFN-gamma, but not IL-4 cytokine production. Depletion of CD8(+) T cells from regressor splenocytes before in vitro stimulation with the relevant peptide abolished their cytolytic activity, while depletion of CD4(+) T cells only partially inhibited CTL generation. Tumor regression induced by DISC/mGM-CSF virus immunotherapy provides a unique model for evaluating the immune mechanism(s) involved in tumor rejection, upon which tumor immunotherapy regimes may be based.
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PMID:Tumor regression induced by intratumor therapy with a disabled infectious single cycle (DISC) herpes simplex virus (HSV) vector, DISC/HSV/murine granulocyte-macrophage colony-stimulating factor, correlates with antigen-specific adaptive immunity. 1190 13


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