Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Use of a recombinant vaccinia virus expressing human interleukin-2 (IL-2) was evaluated for preparation of tumor vaccines. A/J mice were immunized against neuroblastoma (C1300) cells using a preparation of C1300 cells infected/transfected with the recombinant virus, vCF13, expressing IL-2. A second recombinant vaccinia, vSC8, expressing Escherichia coli beta-galactosidase, was used as a control. After three weekly immunizations with virus-transfected cells, the mice were challenged with 1 x 10(6) unmodified C1300 cells and tumor development was monitored. Tumor development in the mice was inhibited by immunization with vCF13-transfected cells, compared to those vaccinated with vSC8-transfected cells (P < .008). A group of mice (7/15) immunized with vCF13-transfected cells followed by tumor challenge survived more than 60 days, at which time all mice immunized with the control vaccine were dead (p < .006). Five of the mice treated with the vCF13 vaccine were alive for more than 75 days (P < .05), after which they were rechallenged with another dose of 1 x 10(6) unmodified tumor cells. Tumor development was not apparent in these mice for more than 45 days following the second challenge, suggesting that these mice were completely protected by this immunization. These results demonstrate that recombinant vaccinia virus expressing IL-2 may be useful for cancer gene therapy.
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PMID:Recombinant vaccinia expressing interleukin-2 for cancer gene therapy. 872 80

Tumor cells genetically modified to express immunostimulatory molecules can produce high levels of antitumor immunity in rodent models. Although a number of clinical trials are currently in progress to assess the value of the approach in human disease, almost all require ex vivo transduction of cultured tumor cells with retroviral vectors. This process is not feasible for many human malignancies, hampering clinical evaluation of the approach. We have used an E1a,1b/E3 deletion mutant of adenovirus containing either the lacZ or the human interleukin-2 (IL-2) gene to transduce human neuroblastoma cells. This vector transduces fresh neuroblastoma cells and neuroblastoma cell lines with an efficiency of 80-90%, compared to an efficiency of 0-14% obtained with retroviral vectors. Cells transduced with the IL-2 adenovector produce up to 12,000 pg of IL-2/10(6) cells/24 hr. IL-2 adenovector-transduced neuroblasts are immunostimulatory; when they are cultured with patient lymphocytes, they increase the proportion of DR+ T cells and generate major histocompatibility complex (MHC) unrestricted cytotoxic effector cells active against parental (nontransduced) tumor cells. We conclude that IL-2 adenovector can be used to transduce freshly isolated human tumor cells efficiently, which will then produce immunomodulatory quantities of the cytokine. The use of adenoviral rather than retroviral vectors facilitates preparation of human tumor "vaccines" and these vectors are now being used in our clinical study of neuroblastoma patients.
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PMID:High-efficiency transduction of freshly isolated human tumor cells using adenoviral interleukin-2 vectors. 879 47

Despite intensified chemotherapy protocols, including autologous bone marrow transplantation (ABMT), stage IV neuroblastoma has a poor prognosis, and modern therapeutic trends are aimed at the eradication of minimal residual disease, which is though to be the main factor leading to relapse. In this pilot study, we report the systemic administration of high doses of interleukin-2 after ABMT in four patients. Five day cycles of IL-2 at a dose of 18 x 10(6) IU/m2/day were administered at variable time intervals as frequent as it was necessary to maintain the levels of natural killer (NK) cytotoxic activity higher than the median control value (40 LU/ml blood) throughout 1 year from the start of first IL-2 treatment. After IL-2 infusion, NK and LAK activities increased significantly (median 742 x 10(-3) LU/ml blood and 186.8 x 10(-3) LU/ml blood, respectively). Toxicities were transient and no life-threatening complications were observed. Fever, anorexia, skin rash and enlarged liver were always present. Anaemia, thrombocytopenia, leukocytosis, lymphocytosis and and eosinophilia occurred following most of the IL-2 courses. Although the small number of patients does not allow an estimation of the immunomodulatory-antineoplasic effects of IL-2, the results seem promising for the management of neuroblastoma patients.
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PMID:High-dose systemic interleukin-2 therapy in stage IV neuroblastoma for one year after autologous bone marrow transplantation: pilot study. 888 13

The neuroblastoma x glioma hybrid cell line NH15-CA2 was used to test the effects of two interleukins on neuronal Na+ channels. The cells were cultured in the presence of dibutyryl cAMP and retinoic acid, which yielded a high expression of Na+ channels so that the cells were excitable. Na+ currents were triggered and recorded in the whole-cell recording mode. Comparison of the effects of tetrodotoxin and mu-conotoxin established that the expressed Na+ channels were of the neuronal type. Bath-applied recombinant human interleukin-2 (rIL-2) had a reversible inhibitory effect on the Na+ currents, although to a lesser extent than on muscular Na+ currents (more than 1000 U/ml required for 50% block in NH15-CA2 cells vs 500 U/ml in myoballs). The current/voltage relationship was not affected by the presence of rIL-2, but the steady-state inactivation curve was shifted by -7.7 +/- 4.8 mV (mean +/- SD, n=18). Recombinant human interleukin-1beta (rIL-1beta), applied at 1000 U/ml, showed an inhibitory effect on the Na+ currents in about one-third of the cells tested. The mechanism of inhibition was different from that of rIL-2, as rIL-1beta seemed to cause a block without affecting voltage dependence or kinetics of the channels.
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PMID:Excitatory sodium currents of NH15-CA2 neuroblastoma x glioma hybrid cells are differently affected by interleukin-2 and interleukin-1beta. 901 18

In this study, we examined the therapeutic antitumor effect of cytotoxic T lymphocytes (CTL) generated against CD86-transfected mouse neuroblastoma C1300. We first generated the transfectant, CD86 + C1300, expressing a high level of mouse CD86 on the cell surface. While CD86 + C1300 cells were rejected in syngeneic A/J mice when inoculated subcutaneously, neither vaccination nor any therapeutic antitumor effect was obtained, implying that C1300 may be a poorly immunogenic tumor. However, in vitro stimulation of splenocytes from either C1300-bearing or CD86 + C1300-rejecting mice with CD86 + C1300 cells resulted in remarkable CTL activity against C1300 cells. The CTL activity induced by CD86 + C1300 was mediated by T cell receptor/CD3 and CD8 and was further enhanced by the addition of interleukin-2. Intravenous inoculation of C1300 cells led to multiple organ metastases including the liver, lung, kidney, ovary, lymph node and bone marrow. To examine the therapeutic effect of CTL in this metastasis model, CTL induced by parental or CD86 + C1300 cells were administrated into C1300-bearing mice. Adoptive transfer of CD86 + C1300-induced CTL resulted in marked elimination of multi-organ metastases and prolonged survival in almost all mice, 70% of which survived indefinitely. These results indicate that adoptive transfer of CTL induced by CD86-transfected tumor cells in vitro would be effective and useful for tumor immunotherapy against poorly immunogenic tumors.
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PMID:Adoptive transfer of cytotoxic T lymphocytes induced by CD86-transfected tumor cells suppresses multi-organ metastases of C1300 neuroblastoma in mice. 922 78

Recently the high transfection potential of the cationic polymer polyethylenimine (PEI) was described (Boussif O et al. Proc Natl Acad Sci USA 1995; 92: 7297-7301). To combine the promising DNA delivering activity of PEI with the concept of receptor-mediated gene delivery, cell-binding ligands (transferrin or antiCD3 antibody) were incorporated by covalent linkage to PEI. DNA complexes of PEI or ligand-PEI conjugates were tested for transfection of cultured neuroblastoma Neuro 2A cells, melanoma B16 or H225 cells, erythroid leukemic K562 cells and T cell leukemia Jurkat E6.1 cells. Depending on the cell line, incorporation of the cell-binding ligand resulted in an up to 1000-fold increased transfection efficiency. This activity depends on ligand-receptor interaction and was observed also at low PEI cation:DNA anion ratios where ligand-free PEI lacks efficiency. Depending on the cell-binding ligand, specific targeting (CD3 antibody, Jurkat cells) can be achieved. Gene transfer can be augmented by the addition of an endosome-destabilizing influenza peptide, but is not dependent on the presence of additional endosomolytic agents. Application of transferrin-PEI for the production of murine interleukin-2 in B16 cells resulted in exceptionally high secretion rates of 19 micrograms IL-2 protein per 10(6) cells per 24 h.
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PMID:Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. 927 17

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.
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PMID:Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. 947 37

Immunization of cancer patients with cytokine-engineered tumor cells is being currently tested in several trials. To test the feasibility of this approach in neuroblastoma (NB) patients we investigated the functional consequences of interleukin-2 (IL-2) gene transfer into NB cell lines. Two human NB cell lines were transfected with the plasmid expression vector RSV.5neo containing the human IL-2 cDNA, and their tumorigenicity was evaluated in a nude mice xenograft model after characterization of the growth patterns and phenotypic features in vitro. The combination of IL-2 gene transfection and the xenograft model in nude mice was chosen on the basis of the low or absent expression of HLA class I antigen in human NB tumors. Our aim was to evaluate the effectiveness of an immunization protocol that could elicit a nonspecific antitumor response. The IL-2 stable transfectants were morphologically identical to parental or vector-transfected cells but completely lost tumorigenicity and inhibited, through a bystander effect, the growth of parental cells injected simultaneously at the same site. Histologic and immunohistochemical analysis of the nodules showed extensive necrosis with severe endothelial damage. The infiltrating cells were mainly macrophages, while natural killer (NK) cells were scarce. However, depletion of NK cells by anti-CD122 monoclonal antibody indicated that the rejection process required NK cell activity. The relevance of these data for the development of therapeutic approaches using cytokine-engineered NB cell lines is discussed.
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PMID:Characterization and tumorigenicity of human neuroblastoma cells transfected with the IL-2 gene. 947 65

We have examined the antitumor effect of murine neuroblastoma cells (C1300) engineered to produce cytokines. Retrovirally transduced cells with human interleukin-2 (IL-2) or murine GM-CSF gene, but not murine IL-4 gene, abolished their tumorigenicity in syngeneic mice, although their in vitro growth rate and expression of class I antigens of the major histocompatibility complex were unchanged. Inoculation of wild-type cells into the mice, which had rejected IL-2 or GM-CSF producers, did not develop tumors, indicating that protective immunity was induced. In an experimental hematogenous metastasis model, we found that the numbers of metastatic foci in the liver caused by intravenous administration of IL-2 or GM-CSF producers were significantly reduced compared with those by the injection of wild-type or vector virus-transduced cells. No significant differences in their adhesiveness to extracellular matrices and ability to differentiate were observed among parent and transduced cells. Thus, these results indicate that IL-2 or GM-CSF secretion, in the vicinity of neuroblastoma cells, produced antitumor effect and reduced metastatic ability.
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PMID:Impaired tumorigenicity and decreased liver metastasis of murine neuroblastoma cells engineered to secrete interleukin-2 or granulocyte macrophage colony-stimulating factor. 957 Feb 97

We have examined vaccination effects of cytokine-producing murine neuroblastoma cells (C1300). C1300 cells retrovirally transduced with interleukin-2 (IL-2) or granulocyte macrophage-colony stimulation factor (GM-CSF) gene were established. Their in vitro proliferation rates and the class I expression of major histocompatibility complex were not different from those of wild-type cells. Five-Gy irradiation of the respective cytokine producers slightly reduced the in vitro cell growth but treatment with 15 Gy significantly impaired the proliferation. In contrast, the secretion of both cytokines from the respective transduced cells was retained compared with the cell growth. We immunized syngeneic mice with irradiated wild-type cells as a control or cytokine-producing cells and challenged the mice with unirradiated wild-type cells. The control mice developed tumors of the challenged wild-type cells, on the contrary, the mice which had received irradiated IL-2 or GM-CSF producers did not. Thus, IL-2- or GM-CSF-expressing syngeneic tumor cells can be potentially used as a tumor vaccine by inducing protective immunity against low immunogenic neuroblastomas in the inoculated hosts.
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PMID:Antitumor vaccine effect of irradiated murine neuroblastoma cells producing interleukin-2 or granulocyte macrophage-colony stimulating factor. 962 5


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