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    ABSTRACT: The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (iNOS) can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma metastases. Liver metastases were established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) containing the lipopeptide CGP 31362 (MLV-31362) or MLV-31362 combined with murine IFN-gamma eradicated the metastases. Tumor regression correlated with iNOS expression within the tumor lesions detected by Northern blot and immunohistochemistry techniques and with increased production of nitric oxide (NO). The administration of a specific iNOS inhibitor, NG-methyl-L-arginine, significantly decreased NO production and diminished the antitumor activities of the immunomodulators. Consistent with the regression of hepatic metastases, the combination of MLV-31362 and IFN-gamma synergistically induced iNOS gene expression, NO production, and apoptosis in the tumor cells under in vitro and in vivo conditions. The addition of NMA prevented the production of NO and apoptosis. These data imply that multiple systemic administrations of MLV-31362 plus IFN-gamma activate endogenous iNOS in sarcoma cells, which then undergo apoptosis, leading in turn to the regression of M5076 sarcoma hepatic metastases.
    Cancer Research 08/1995; 55(14):3123-31. · 8.65 Impact Factor
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    ABSTRACT: Cancer vaccines targeting CD8+ T cells have been successful in eliciting immunologic responses but disappointing in inducing clinical responses. Strong evidence supports the importance of CD4+ T cells in "helping" cytotoxic CD8+ cells in antitumor immunity. We report here on two consecutive clinical trials evaluating the impact of immunization with both human leukocyte antigen class I- and class II-restricted peptides from the gp100 melanoma antigen. In Protocol 1, 22 patients with metastatic melanoma were immunized with two modified class I A*0201-restricted peptides, gp100:209-217(210M) and MART-1:26-35(27L). In Protocol 2, 19 patients received the same class I-restricted peptides in combination with a class II DRB1*0401-restricted peptide, gp100:44-59. As assessed by in vitro sensitization assays using peripheral blood mononuclear cells (PBMC) against the native gp100:209-217 peptide, 95% of patients in Protocol 1 were successfully immunized after two vaccinations in contrast to 50% of patients in Protocol 2 (P(2) < 0.005). Furthermore, the degree of sensitization was significantly lower in patients in Protocol 2 (P = 0.01). Clinically, one patient in Protocol 2 had an objective response, and none did in Protocol 1. Thus, the addition of the class II-restricted peptide gp100:44-59 did not improve clinical response but might have diminished the immunologic response of circulating PBMC to the class I-restricted peptide gp100:209-217. The reasons for this decreased immune reactivity are unclear but may involve increased CD4+CD25+ regulatory T-cell activity, increased apoptosis of activated CD8+ T cells, or the trafficking of sensitized CD8+ reactive cells out of the peripheral blood. Moreover, the sequential, nonrandomized nature of patient enrollment for the two trials may account for the differences in immunologic response.
    Journla of Immunotherapy 01/2003; 26(4):349-56. · 3.46 Impact Factor
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    ABSTRACT: Recombinant glycoprotein B (gB) of herpes simplex virus (HSV) was processed and presented by class I major histocompatibility complex (MHC) molecules after delivery into cells by using N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate (DOTAP), a commercially available cationic lipid used for DNA transfection. Cells treated with DOTAP-associated gB were susceptible to lysis by class I MHC-restricted, HSV-specific cytotoxic T lymphocytes (CTL), and the treated cells restimulated memory gB-specific CTL activity in spleen cells from HSV-infected mice. gB-specific CTL responses were detected in mice immunized with recombinant gB and DOTAP but not in those receiving gB emulsified in complete Freund's adjuvant. Thus, cationic lipids may facilitate induction of CD8+ T-cell responses in vaccinations with recombinant antigens, and they may serve as readily available reagents for dissecting class I MHC immunity to viruses and other intracellular pathogens.
    Proceedings of the National Academy of Sciences 10/1992; 89(17):7915-8. · 9.81 Impact Factor

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