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)

Recently, several studies have shown that vaccine therapy using dendritic cells (DCs) genetically engineered to express a surrogate tumor antigen can effectively induce antitumor immunity. In this study, murine bone marrow DCs were adenovirally transduced with murine endogenous tumor antigen gp70 expressed in CT26 cells and granulocyte macrophage colony-stimulating factor (GM-CSF), and we examined whether antigen-specific CTL responses and therapeutic immunity could be induced in mice immunized with those genetically modified DCs. The cytotoxic activity against CT26 in mice immunized with gp70-transduced DCs was significantly higher than that in control (P < 0.01) and was enhanced by GM-CSF-cotransduction (P < 0.001). GM-CSF gene transfer into DCs expressing tumor-associated antigen enhances CC chemokine receptor 7 expression on DCs, leading to improved migratory capacity of DCs to draining lymph nodes. Consequently, an effective antitumor immune response would be induced. Vaccination using gp70-transduced DCs provided remarkable therapeutic efficacy in s.c. models. Moreover, it could be sufficiently augmented by GM-CSF-cotransduction of DCs. These results support that vaccination therapy using DCs simultaneously transduced with tumor-associated antigen can elicit potent CTL response, and GM-CSF-cotransduction of DCs could optimize therapeutic response. Further investigation is needed to optimize this vaccine therapy to achieve the obvious benefit in clinical application.
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PMID:Dendritic cells genetically engineered to simultaneously express endogenous tumor antigen and granulocyte macrophage colony-stimulating factor elicit potent therapeutic antitumor immunity. 1217 8

DNA vaccines can activate immunity against tumor Ags expressed as MHC class I-associated peptides. However, priming of CD8(+) CTL against weak tumor Ags may require adjuvant molecules. We have used a pathogen-derived sequence from tetanus toxin (fragment C (FrC)) fused to tumor Ag sequences to promote Ab and CD4(+) T cell responses. For induction of CD8(+) T cell responses, the FrC sequence has been engineered to remove potentially competitive MHC class I-binding epitopes and to improve presentation of tumor epitopes. The colon carcinoma CT26 expresses an endogenous retroviral gene product, gp70, containing a known H2-L(d)-restricted epitope (AH1). A DNA vaccine encoding gp70 alone was a poor inducer of CTL, and performance was not significantly improved by fusion of full-length FrC. However, use of a minimized domain of FrC, with the AH1 sequence fused to the 3' position, led to rapid induction of high levels of CTL. IFN-gamma-producing epitope-specific CTL were detectable ex vivo and these killed CT26 targets in vitro. The single epitope vaccine was more effective than GM-CSF-transfected CT26 tumor cells in inducing an AH1-specific CTL response and equally effective in providing protection against tumor challenge. Levels of AH1-specific CTL in vivo were increased following injection of tumor cells, and CTL expanded in vitro were able to kill CT26 cells in tumor bearers. Pre-existing immunity to tetanus toxoid had no effect on the induction of AH1-specific CTL. These data demonstrate the power of epitope-specific CTL against tumor cells and illustrate a strategy for priming immunity via a dual component DNA vaccine.
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PMID:Critical components of a DNA fusion vaccine able to induce protective cytotoxic T cells against a single epitope of a tumor antigen. 1224 89

The major histocompatibility complex class I-restricted CD8(+) cytotoxic T-lymphocyte (CTL) effector arm of the adaptive immune response can specifically recognize and destroy tumor cells expressing peptide antigens. Although adoptive T-cell therapy has been successfully used for the treatment of viral and malignant diseases, little is known of the trafficking and fate of adoptively transferred antigen-specific T cells. In the present study, splenocytes derived from mice that rejected their tumors (CT26 or CT26-clone 25 tumors) in response to direct intratumor injection of disabled infectious single-cycle herpes simplex virus (DISC-HSV) encoding murine GM-CSF were restimulated with peptide in vitro. CTLs specific for the AH-1 and beta-gal peptides expressed by CT26 and CT26-clone 25 tumor cells, respectively, were generated and used for adoptive cellular therapy and trafficking studies. Intravenous administration of AH-1-specific CTLs 3 days following i.v. injection of CT26 cells resulted in significant tumor growth inhibition, whereas administration of control CTLs generated against a bacterial beta-gal peptide did not inhibit the growth of tumors. Trafficking of AH-1-specific lymphocytes and their interaction with the CT26 tumor microcirculation was analyzed using real-time in vivo microscopy (IVM). AH-1-specific but not beta-gal-specific CTLs adhered and localized in the CT26 tumor microvasculature, but neither population adhered to the endothelium of the normal microcirculation. This study provides direct visual evidence suggesting that AH-1-specific CTLs that mediate a therapeutic response traffic to and localize within the tumor microenvironment.
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PMID:Trafficking of tumor peptide-specific cytotoxic T lymphocytes into the tumor microcirculation. 1506 88

We evaluated the antitumor effects of combination gene therapy on CT26 mouse colon cancer cells, using the genes for herpes simplex virus thymidine kinase gene HSV-TK combined with granulocyte macrophage colony-stimulating factor (GM-CSF) compared with HSV-TK alone. Cells, unmodified or retrovirally transduced with HSV-TK or GM-CSF, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSV-TK and GM-CSF were also delivered using different routes (in separate cells vs doubly transfected single cells). Both HSV-TK (with i.p. ganciclovir - GCV - treatment) and GM-CSF genes had independent antitumor effects, and given together they caused significant reduction in tumor volumes compared with the HSV-TK gene alone (P < 0.001). Following GCV treatment, however, the treated/control ratios for tumor volumes were not different between tumors containing either HSV-TK alone or both genes (0.27 vs 0.25, respectively). Thus, the presence of GM-CSF did not increase the bystander effect of HSV-TK. Tumors receiving genes transferred in separate cells tended to be more consistently suppressed after GCV treatment than when both genes were transferred in the same cells, although this was not statistically significant. Thus, combination GM-CSF and HSV-TK gene therapy produced greater therapeutic efficacy than HSV-TK alone, but the bystander effect was not enhanced by GM-CSF.
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PMID:Herpes simplex virus thymidine kinase and granulocyte macrophage colony-stimulating factor combination gene therapy in a murine CT26 cell colon cancer model. 1523 2

The potential therapeutic benefit of introducing IFN-gamma and GM-CSF genes in combination with the HSVtk suicide gene into subcutaneously implanted CT26 tumor cells was compared with that from each treatment alone. Cells, unmodified or retrovirally transduced with HSVtk or IFN-gamma/GM-CSF genes, were inoculated subcutaneously into syngeneic BALB/c mice in various combinations. HSVtk gene, with intraperitoneal ganciclovir treatment, reduced tumor volume by 81% at locally inoculated tumor sites (p < 0.01) and by 25% at distantly inoculated tumor sites (p = 0.052). IFN-gamma/GM-CSF genes showed a 56% tumor volume reduction at local tumor sites (p < 0.01) and 15% volume reduction at remote tumor sites, although this was not statistically significant. The combination of HSVtk (with GCV) and IFN-gamma/GM-CSF genes showed an 81% volume reduction at local tumor sites (p < 0.01) and a 43% volume reduction at remote tumor sites (p < 0.01). Thus, the combination of HSVtk and IFN-gamma/GM-CSF gene therapy produced greater therapeutic efficacy than either treatment alone.
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PMID:Increased anti-tumor effect by a combination of HSV thymidine kinase suicide gene therapy and interferon-gamma/GM-CSF cytokine gene therapy in CT26 tumor model. 1636 99

The T-helper 1 (Th1) immune reaction is most important in dendritic cell (DC)-based immunotherapy. Interleukin 12 (IL-12) and granulocyte macrophage colony-stimulating factor (GM-CSF) play a pivotal role in inducing Th1 and cytotoxic T lymphocyte (CTL) responses. In this study, DCs expressing the natural tumor antigen gp70 of BALB/c-derived CT26 were adenovirally transduced with the IL-12 gene and/or GM-CSF gene, and it was examined whether vaccinations using these genetically engineered DCs can induce strong therapeutic antitumor immunity. Mice were immunized once by subcutaneous (s.c.) injection with genetically modified DCs. The cytotoxic activity of splenocytes against CT26 was assayed in a 51Cr-release assay 14 days after immunization. The therapeutic efficacy of the vaccination was examined in s.c. tumor models. The cytotoxic activity of CTLs against CT26 in mice immunized with DCs expressing gp70 (DC-AxCAgp70) was significantly augmented by co-transduction with the GM-CSF/IL-12 gene (p<0.0001) and remarkably reduced by the depletion of CD4+ or CD8+ cells (p<0.01). The cytotoxic activity against CT26 of the plain spleen cells in mice immunized with DC-AxCAgp70/GM-CSF/IL-12 was significantly higher than that in mice immunized with DC-AxCAgp70 (p<0.0001), and this activity decreased to almost 50% upon the depletion of NK cells. Vaccinations using DC-AxCAgp70/GM-CSF/IL-12 or DC-AxCAgp70/IL-12 could elicit potent therapeutic immunity in s.c. tumor models; tumor-free mice were observed in these vaccination groups. However, there was no significant difference between these two groups. A vaccination therapy using DCs co-transduced with the TAA gene and Th 1-type cytokine genes, especially the IL-12 gene, is ideal for immunotherapy in terms of the activation of DCs, NK cells, CD4+ T cells and CD8+ T cells, and may be useful in the clinical application of a cancer vaccine therapy.
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PMID:The boosting effect of co-transduction with cytokine genes on cancer vaccine therapy using genetically modified dendritic cells expressing tumor-associated antigen. 1652 45

We have previously generated antihuman HER2/neu-humanized IgG3 fused to interleukin-2 (IL-2), IL-12, or granulocyte macrophage colony-stimulating factor (GM-CSF) [monofunctional fusion proteins (mono-AbFP)] or fused to IL-2 and IL-12 or IL-12 and GM-CSF [bifunctional fusion proteins (bi-AbFP)]. These AbFPs retained cytokine and antigen-binding activities. We have now further characterized the AbFPs and determined the heparin-binding activity of the fused cytokines, their ability to trigger IFN-gamma secretion and natural killer (NK) activation, and their direct antitumor efficacy. Flow cytometry revealed heparin-binding activity in the AbFPs containing IL-12 and IL-2, although this activity seems to be decreased in the bi-AbFPs. However, both bi-AbFPs retained the capacity to stimulate IL-12-dependent IFN-gamma secretion in the NK cell line KY-1, and IL-12/IL-2 bi-AbFP induced NK activity in splenocytes. The antitumor effectiveness of bi-AbFPs and mono-AbFP combinations was studied in mice challenged i.p. with three different human HER2/neu murine syngeneic models (D2F2/E2, CT26-HER2/neu, and MC38-HER2/neu). Although a significant variability in the profile of antitumor response was observed in the different tumor models, the combination of IL-12 and GM-CSF mono-AbFPs protected 100% of D2F2/E2-challenged and 75% of CT26-HER2/neu-challenged mice. In contrast, bi-AbFPs protected less than the combination of mono-AbFPs and, in some models, even less than mono-AbFPs alone. However, in all cases, most of long-term survivors showed protection after s.c. rechallenge with the tumors and later with the parental tumors not expressing HER2/neu. These results show that, although the pattern of protection is tumor model dependent, treatments with AbFPs can effectively generate high levels of protection against peritoneal tumors expressing HER2/neu, which may be relevant in patients with primary or metastatic peritoneal carcinomatosis that may be observed in ovarian, colon, stomach, bladder, lung, and breast cancers.
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PMID:Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors. 1664 75

Cytokine targeting to tumor-associated antigens via antibody cytokine fusion proteins has demonstrated potent antitumor activity in numerous animal models and has led to the clinical development of 2 antibody-interleukin-2 (IL-2) fusion proteins. We previously reported on the construction and in vitro properties of a "dual" cytokine fusion protein for simultaneous targeted delivery of human granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-2 to human tumors. The fusion protein is based on a heterodimerized core structure formed by human CH1 and Ckappa domains (heterominibody) with C-terminally fused human cytokines and N-terminally fused single-chain antibody fragments specific for the tumor-associated surface antigen epithelial cell adhesion molecule (Ep-CAM). For testing the antitumor activity in syngeneic mouse xenograft models, we developed "dual cytokine heterominibodies" with murine cytokines (mDCH). mDCH fusion proteins and, as controls, "single cytokine heterominibodies" (SCH) carrying either murine GM-CSF (mGM-CSF) or murine IL-2 (mIL-2) were constructed, of which all retained the specific activities of cytokines and binding to the Ep-CAM antigen on human Ep-CAM transfected mouse colon carcinoma CT26-KSA cells. Over a 5-day treatment course, DCH fusion proteins induced significant inhibition of established pulmonary CT26-KSA metastases in immune-competent Balb/c mice at low daily doses of 1 mug of fusion protein per mouse. However, with the tested dosing schemes, antitumor activity of mDCH was largely independent of cytokine targeting to tumors as demonstrated by a control protein with mutated Ep-CAM binding sites. Single cytokine fusion proteins mSCH-GM-CSF and mSCH-IL-2 showed similar antitumor activity as the dual cytokine fusion protein mDCH, indicating that GM-CSF and IL-2 in one molecule did not significantly synergize in tumor rejection under our experimental conditions. Our results seem to contradict the notion that IL-2 and GM-CSF can synergize in antitumor activity and that with conventional dose regimens, their specific targeting to tumors, as tested here with 2 antibodies of different affinities, enhances their antitumor activity.
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PMID:Antitumor activity of a dual cytokine/single-chain antibody fusion protein for simultaneous delivery of GM-CSF and IL-2 to Ep-CAM expressing tumor cells. 1697 4

We have previously reported that the antibody fusion proteins anti-HER2/neu IgG3 fused to IL-12 [(IL-12)-IgG3] or GM-CSF [IgG3-(GM-CSF)] independently or in combination are effective anti-tumor agents against D2F2/E2 murine mammary cancer cells expressing human HER2/neu in the peritoneum. Importantly, the long-term survivors were immune to the subcutaneous challenge with D2F2/E2 and the parental D2F2 not expressing HER2/neu. We now show that these long-term survivors also exhibit significant protection against subsequent subcutaneous challenge with the murine colon carcinoma CT26-HER2/neu, and later against subcutaneous challenge with the parental CT26. These results suggest that the long-term systemic protection against mammary cancer elicited by treatment with antibody-cytokine fusion proteins can be extended to prevent the growth of a tumor from different origin expressing HER2/neu, and that this protection is not limited to this antigen alone, since it also prevented the growth of the parental tumor cells.
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PMID:Long-term immunity elicited by antibody-cytokine fusion proteins protects against sequential challenge with murine mammary and colon malignancies. 1731 Mar 81

Direct viral infection of solid tumors can cause tumor cell death, but these techniques offer the opportunity to express exogenous factors to enhance the antitumor response. We investigated the antitumor effects of a herpes simplex virus (HSV) amplicon expressing mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) using the replication-competent HSV type 1 mutant HF10 as a helper virus. HF10-packaged mGM-CSF-expressing amplicon (mGM-CSF amplicon) was used to infect subcutaneously inoculated murine colorectal tumor cells (CT26 cells) and the antitumor effects were compared to tumors treated with only HF10. The mGM-CSF amplicon efficiently replicated in CT26 cells with similar oncolytic activity to HF10 in vitro. However, when mice subcutaneously inoculated with CT26 cells were intratumorally injected with HF10 or mGM-CSF amplicon, greater tumor regression was seen in mGM-CSF amplicon-treated animals. Furthermore, mGM-CSF amplicon treatment prolonged mouse survival. Immunohistochemical analysis revealed increased inflammatory cell infiltration in the solid tumor in the mGM-CSF amplicon-treated animals. These results suggest that expression of GM-CSF enhances the antitumor effects of HF10, and HF10-packaged GM-CSF-expressing amplicon is a promising agent for the treatment of subcutaneous tumors.
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PMID:Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus. 1769 92


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