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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gp100 melanoma-associated tumor Ag was selected as a model system to study the diversity of human antitumor cytotoxic T cell responses. First, peptides corresponding to dominant gp100 HLA-A2.1-restricted CTL epitopes were tested using lymphocytes from normal volunteers and an in vitro priming protocol that uses peptide-pulsed dendritic cells as APCs and IL-7 and IL-10 as immune-enhancing cytokines. High CTL activity toward both peptide-pulsed target cells and gp100+ melanoma cells was obtained with four out of five peptides tested. Second, HLA-A2.1-binding peptides from gp100 that do not appear to represent CTL epitopes in melanoma patients were also tested for their capacity to induce CTL using the in vitro priming protocol. Three of six peptides tested induced CTL in lymphocytes from normal volunteers. One of these peptides was also immunogenic for lymphocytes derived from a melanoma patient in remission. Because these three CTL epitopes were not recognized in the natural immune response in melanoma patients but do appear as immunogens when peptides are used to induce the T cell response, they may be considered as typical "subdominant" epitopes. The results are discussed in the context of the usefulness of this approach to detail the immunologic potential of a given tumor-associated Ag and its relevance for the design of effective immune-based therapies.
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PMID:Identification of subdominant CTL epitopes of the GP100 melanoma-associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. 902 18

We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rIL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production, and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10(5) IU/m2 of rIL-2 (0.03 mg/m2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day 1 and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-alpha). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta 2, and sIL-2R-alpha by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day 1, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the beta-phase, during which IL-2 concentrations were sustained at approximately 10-30 ng/ml (day 1 and day 4) and the median t1/2 beta was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-gamma and sIL-2R-alpha were observed on day 4. (IFN-gamma 217 pg/ml; sIL2-R-alpha: 3486 U/ml). No increases in TNF-alpha or TGF-beta 2 were observed. Large increases in p.c. CD3+, CD4+, CD8+, CD16+, and CD56+ cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m2.
J Immunother Emphasis Tumor Immunol 1996 Nov
PMID:Immunopharmacology and cytokine production of a low-dose schedule of intraperitoneally administered human recombinant interleukin-2 in patients with advanced epithelial ovarian carcinoma. 904 64

Identifying target antigens for tumor-reactive T cells is important for understanding the mechanisms of tumor escape and developing novel anticancer therapies. To date, mainly CTL responses from tumor infiltrating associated lymphocytes (TIL/TAL) to peptide antigens have been investigated in ovarian cancer. In the present study, the ability of self-peptides derived from HER-2/neu proto-oncogene product (HER-2) to stimulate proliferation of PBMC from healthy donors and ovarian cancer patients has been assessed. Peptide sequences from HER-2 containing anchors for major human MHC-class II molecules have been identified. These peptides induced proliferative and cytokine responses at higher frequency in healthy donors than ovarian cancer patients. Four HER-2 peptides corresponding to positions: 396-406, 474-487, 777-789, and 884-899 were able to stimulate proliferation of a larger number of healthy donors than three other distinct HER-2 peptides 449-464, 975-987 and 1086-1098. The pattern of responses of twenty five ovarian cancer patients was different from that in healthy donors. T cell lines were developed by stimulation with peptides from PBMC of an ovarian cancer patient who showed a stable response to all four HER-2 peptides for over six months. Each T cell line was different in its ability to secrete IFN-gamma and IL-10. These results demonstrate (a) that self-peptides from HER-2 can stimulate expansion of T cells in both healthy donors and ovarian cancer patients, and (b) the ability of different peptides to stimulate secretion of different cytokines from lymphocytes of ovarian cancer patients. These results may be important for understanding the mechanisms of tolerance and autoimmunity in human cancers.
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PMID:Existent proliferative responses of peripheral blood mononuclear cells from healthy donors and ovarian cancer patients to HER-2 peptides. 906 29

Determinants of T cell responses to tumor cells remain largely unknown. In the present study we have used long-term cultures of human melanoma cells and autologous peripheral blood lymphocytes to examine the influence of cytokines with T cell growth activity on the phenotype and cytotoxic and proliferative response of T cells to melanoma. It was found that addition of interleukin-4 (IL-4) inhibited the response of CD8+ T cells and promoted the response of the CD4 subset. IL-2 or IL-7 was effective in increasing melanoma-specific cytotoxic T lymphocyte (CTL) activity in cultures where CD8 T cells were predominant, whereas IL-4 followed by IL-2 was most effective in cultures where CD4 T cells predominated. IL-10 or IL-12 inhibited proliferation and CTL activity against melanoma in long-term cultures. The effects of IL-12 were reproduced in long-term cultures of T cells stimulated with mAb against CD3 and were shown to depend on prior exposure of T cells to IL-12 before IL-2. As yet unidentified factors, such as co-factor expression on melanoma, appear to be as important as exogenous cytokines in determining the nature of T cell responses to melanoma. These results suggest that analysis of responses in long-term culture may assist in defining the role of key cytokines and other determinants of immune responses to melanoma.
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PMID:Contrasting effects of T cell growth factors on T cell responses to melanoma in vitro. 906 6

Tumor regression in experimental systems has been linked to the activities of Th1 cells. It is, therefore, conceivable that Th2 cells interrupt the expression of tumor immunity since interleukin-4 (IL-4) and IL-10 inhibit the generation of Th1 from precursors and modulate the competence of antigen-presenting cells to activate this lymphocyte subpopulation. Naive murine renal cell carcinoma (renca) cells (1 x 10(5)) were implanted into the subcapsule of the left kidney of Balb/c and Balb/c nude mice at 6-8 weeks of age. After 14 days, Th2 cytokine (IL-4 and IL-10) mRNAs as well as transforming growth factor beta1 mRNA, assessed by reverse transcriptase/polymerase chain reaction were upregulated in the spleen of hosts upon naive renca tumor acceptance, while Th1 cytokine (IL-2 and interferon gamma) mRNAs were almost undetectable. In the renca tumor, IL-10 mRNA was detected but IL-2, interferon gamma, and IL-4 were not. Intraperitoneal administration of anti-(mouse IL-4) mAb (11B11) reduced the renca tumor size (P = 0.018) and prolonged host survival (P = 0.03), but did not reduce the acceptance rate of the tumor (P = 0.18). However, prior depletion of CD4+ or CD8+ cells with monoclonal antibodies abrogated the antitumor effects of anti-IL-4 mAb. In addition, the significant antitumor effect of anti-IL-4 mAb was not observed in Balb/c nude hosts. Renca cells were transfected with the mammalian expression vector pCAGGS containing murine IL-4 cDNA or vector alone, then stable IL-4 transfectants (RencaL or RencaH, low- or high-IL-4-producing respectively) and control renca cells (RencaC) were obtained. RencaL cells, RencaH cells, or RencaC cells (1 x 10(5) each) were implanted into the subcapsule of the left kidney of Balb/c, Balb/c nude, and allogenic C3H/HeJ mice, then tumor formation was evaluated 14 days later. When RencaH cells were innoculated into syngeneic Balb/c hosts, tumor volume was marginally suppressed (P = 0.03) and tumors tended to be rejected (P = 0.06) compared with RencaC cells. However, those effects were not observed in Balb/c nude mice. RencaC, RencaL, and RencaH cells were not accepted by allogeneic C3H mice with or without FK506 administration or donor-specific transfusion. The administration of anti-(mouse IL-4) mAb to Balb/c mice significantly suppressed renca tumor growth by a CD4+ and CD8+ T-cell-dependent mechanism. By contrast, relatively high levels of IL-4 production by renca cells and T cells seemed to be required to induce the rejection and growth suppression of IL-4-producing renca cells in syngeneic hosts.
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PMID:Th2-like response and antitumor effect of anti-interleukin-4 mAb in mice bearing renal cell carcinoma. 906 10

Although IL-12 possesses the most potent single-cytokine antitumor efficacy, the mechanism by which IL-12 exerts its antitumor activities remains unclear. Using a complete tumor regression model induced by IL-12 treatment, we demonstrate that the antitumor response induced by IL-12 is mediated by a Th1 cell-directed process, with the macrophage as the effector cell and nitric oxide produced by the activated macrophage as the effector molecule. The induction of the Th1 response by IL-12 depends on the existence of a host T cell response to the tumor before IL-12 administration. IL-12 treatment causes the complete regression of 10-day established s.c. tumors (4-8 mm). Associated with the induction of tumor necrosis, activated macrophages expressing high levels of inducible nitric oxide synthase were found surrounding the tumor. The importance of nitric oxide as the effector molecule was further confirmed by the delay and loss of tumor regression in the presence of a nitric oxide synthase inhibitor in vivo. Examination of tumor-associated T cells indicates that IL-12 induces production of the Th1 cytokine IFN-gamma and suppresses production of IL-2, IL-4, and IL-10 at the tumor site, where these are found to be the predominant cytokines produced by tumor-associated T cells before IL-12 treatment. These findings demonstrate that IL-12 plays an essential role in the induction of an effective Th1 type of cell-mediated immune response against established tumors.
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PMID:IL-12 induces T helper 1-directed antitumor response. 912 Feb 94

To investigate the mechanisms of T cell dependence underlying the development of extranodal mucosa-associated lymphoid tissue (MALT)-type B cell lymphomas, the activation, proliferation, and differentiation of lymphoma B cells were studied using ligand binding to the CD40 membrane receptor. The activation and proliferative response of all investigated low-grade MALT-type lymphomas (n = 6) was strongly dependent on anti-CD40-mediated signals and was complemented by cytokines produced by T helper cells of the Th2 type (interleukin-4 (IL-4) and/or IL-10). Th1 cytokines (IL-2 and/or interferon-gamma) bad little effect. Low-grade, but less so high-grade, MALT-type lymphoma B cells were induced to secrete large amounts of tumor immunoglobulin in response to IL-10. In contrast, high-grade MALT-type lymphomas (n = 5) proliferated in response to both Th2- and Th1-type cytokines and CD40 stimulation, whereas Burkitt lymphomas (n = 3) could not be rescued from apoptosis by CD40 stimulation with or without cytokines. These results suggest that CD40 signaling in combination with Th2 cytokines are essential for the development and progression of low-grade MALT-type B cell lymphoma. We conclude that T cells, which activate B cells in a CD40-dependent fashion, may contribute to lymphoma pathogenesis.
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PMID:Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. 913 85

We studied several in vitro activities of tumor-associated lympho-monocytes (TALMs) and the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)alpha, interferon (IFN)gamma and soluble IL-2 receptor (slL-2R) in neoplastic effusions and in the serum of advanced stage cancer patients. Comparisons were made with autologous peripheral blood mononuclear cells (PBMCs). Autologous PBMCs were compared with PBMCs from normal subjects used as controls. TALMs were collected from 13 peritoneal and 18 pleural neoplastic effusions, secondary to primary tumors of different sites. After PHA stimulation, concentrations of IL-1alpha, IL-1beta and TNF alpha in culture media of TALMs both from peritoneal and pleural effusions were lower than those of autologous PBMCs and, similarly, concentrations of IL-4 and IL-10 in culture media of TALMs from peritoneal effusions were lower than those of autologous PBMCs, whereas concentrations of IL-4 and IL-10 in culture media of TALMs from pleural effusions were in the same range as those of autologous PBMCs. On the contrary, IL-2, IL-6 and IFN gamma amounts (only from pleural effusions) were significantly higher. IL-1alpha, IL-1beta, IL-2, IL-6 and TNF alpha production from patient PBMCs was lower than that of control PBMCs, whereas production of IL-4, IL-10 and IFN gamma was higher than that of control PBMCs. Both in peritoneal and in pleural effusions concentrations of IL-1alpha, IL-1beta and IL-4 were not different from those measured in autologous serum, whereas those of IL-6, IL-10, TNF alpha, IFN gamma and sIL-2R were significantly higher. The amounts of IL-2 in pleural effusions were not different from those of autologous serum, but in peritoneal effusions they were higher than those of autologous serum. The amounts of IL-1alpha, IL-1beta, IL-2, IL-6, TNF alpha and sIL-2R were higher in patient than in control sera, whereas those of IL-4, IL-10 and IFN gamma were in the same range in patient and in control sera. Cell cycle analysis of cultured TALMs and PBMCs (from 3 patients) showed a significant accumulation of TALMs in the non-cycling G0/G1 cell population compared with autologous PBMCs.
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PMID:Tumor-associated lympho-monocytes from neoplastic effusions are immunologically defective in comparison with patient autologous PBMCs but are capable of releasing high amounts of various cytokines. 918 Jan 37

Spontaneous tumor regression, which is observed clinically and histologically in some primary melanomas, occurs in the absence of any effective therapy. It is probably immunologically mediated, because regressing melanomas are infiltrated with larger numbers of activated T cells, primarily CD4+, than nonregressing melanomas. To investigate the hypothesis that spontaneous regression of melanomas is caused by T-cell cytokine production, cytokine mRNA expression in 20 primary melanomas was examined using a noncompetitive, quantitative reverse-transcriptase polymerase chain reaction method. DNA standards were used to generate known numbers of molecules in each sample. Results were standardized to the internal control, glyceraldehyde-3-phosphate dehydrogenase. mRNA for CD35, lymphotoxin (TNF-beta), and IL-2 were significantly elevated in the ten regressing melanomas compared to the ten nonregressing melanomas. IFN-gamma mRNA was also elevated in regressing melanomas but failed to reach statistical significance. The Th2 cytokines IL-10 and IL-13 did not show differences in the regressing melanomas compared to nonregressing melanomas; neither did the pro-inflammatory cytokines IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha, nor the growth factors, bFGF and TGF-beta or GM-CSF. This study shows an association between Th1 cytokines and spontaneously regressing melanomas. Although we have not shown that these cytokines cause regression, these findings support our hypothesis that activated CD4+ T cells may mediate melanoma regression by secretion of Th1 cytokines.
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PMID:T helper 1 cytokine mRNA is increased in spontaneously regressing primary melanomas. 918 21

ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have examined the therapeutic effects of ONO-4007 on rat hepatocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 after tumor implantation of KMT-17 cells. ONO-4007 showed significant therapeutic effects on KDH-8 cells; by the administration of ONO-4007 (2.5 mg/kg) 70% of rats were cured and by the administration of ONO-4007 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatment prolonged the mean survival time of KDH-8-bearing rats. However, ONO-4007 had no effect on KMT-17 and SST-2 cells, and it had no direct effect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-a, those of IL-2, IL-4, IL-10 and interferon (IFN)-gamma were not induced. Using a bioassay, we found that the production of TNF-alpha in the tumor tissues was induced by ONO-4007 in a dose-dependent manner. KDH-8 cells were sensitive to human natural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resistant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.
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PMID:A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. 921 14


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