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

Monoclonal antibodies (mAB) with tumor specificity are able to enhance the immunological specificity of interleukin 2 (IL-2)-activated lymphokine activated killer (LAK) cells. Antibodies may also be used to broaden the range of tumor types susceptible to immune mediated cytotoxicity by the activated LAK cells. In these studies, mAB with relative tumor specificity were used to target immunologically activated effector cells in an in vitro antibody dependent cell mediated cytotoxicity (ADCC) assay. The mAB included: 3F8 and 14.G2a, which are both specific for neuroblastoma and melanoma and recognize ganglioside GD2, and mAB ING-1, a mouse-human chimeric antibody with constant regions from human IgG1 and kappa chains and variable regions from a mouse mAB that binds to a broad range of human adenocarcinomas. Each of these mAB was able to mediate ADCC with fresh effector cells and antibody binding targets. When peripheral blood mononuclear cells were obtained from cancer patients prior to and following in vivo therapy with interleukin 2, a significant increase was noted in ADCC activity by peripheral blood mononuclear cells obtained following IL-2 therapy. Inclusion of IL-2 in the medium during the cytotoxic assay with mAB further boosted ADCC. The total activity seen was often greater than the sum of the independent LAK activity and standard ADCC activity. The cells responsible for this ADCC had the CD16+ Fc receptor. Combining IL-2 with mAB in clinical tumor therapy may lead to a wider range of tumor types being responsive to immunotherapy and may also enhance the efficacy of therapy by specifically targeting activated effector cells to tumor cells recognized by mAB. Our results provide strong support for the testing of these hypotheses in clinical trials by combining in vivo treatment with IL-2 and mAB able to mediate ADCC.
 ...
PMID:Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2. 238 33

The presence of neonatal (cord) lymphokine-activated killer (LAK) cell activity toward natural killer cell resistant Raji and Daudi cell lines has recently been reported from our laboratory. We investigated the future therapeutic use of LAK adoptive immunotherapy by examining LAK in vitro cytotoxicity from both neonatal and adult mononuclear cells against solid tumor cell lines of relevance to pediatric oncology: SH-SY5Y (neuroblastoma), SK-NM-C (neuroblastoma-neuroepithelioma), NEP-1 (Wilms' tumor), SK-ES-1 (Ewing's sarcoma), and A-204 (rhabdomyosarcoma). Cord and adult mononuclear cells were activated by recombinant IL-2 (100 mu/ml) for 5-7 days and added in an effector:target ratio of 40:1 to 51Cr-labeled target cells. Specific cell lysis was determined after a 4-h incubation. There was a significantly high level of cord and adult LAK cytotoxicity against Wilms' (76.4 +/- 9.8 versus 77.3 +/- 6.8%) and Ewing's (84.2 +/- 5.5 versus 71.1 +/- 6.5%) cell lines and significant but moderate LAK activity against neuroepithelioma (52.0 +/- 6.6 versus 55.4 +/- 4.5%) and rhabdomyosarcoma (46.6 +/- 5.7 versus 43.9 +/- 5.2%) cell lines. There was no difference between cord and adult LAK activity toward these targets. However, a differential response toward the more classical neuroblastoma cell line, SH-SY5Y, was noted with significantly more LAK cytotoxicity from cord mononuclear cells than adult mononuclear cells (51.2 +/- 6.9 versus 28.5 +/- 8.2%) (p less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Lymphokine-activated killer cytotoxicity in neonatal mononuclear cells: in vitro responses to tumor cell lines from pediatric solid tumors. 253 88

Therapy of disseminated neuroblastoma remains an unsolved problem in pediatric oncology. Therefore, new therapeutic approaches have to be developed for this malignancy. In this paper, we investigated the possibility of the in vitro generation and expansion of lymphokine-activated killer (LAK) cells in patients with disseminated neuroblastoma. Although the patients had very low Natural Killer (NK) activity, it was possible to induce LAK activity in peripheral mononuclear lymphocytes (PMNC) by incubation with Interleukin-2 (IL-2). Moreover, the PMNCs could be expanded up to 50-fold in the presence of Interleukin-2 while maintaining or even increasing their LAK activity. The target cells were neuroblastoma cell lines and, in one case, autologous neuroblastoma cells. Additionally, it was possible to induce LAK cell activity against autologous neuroblastoma cells in bone marrow-derived mononuclear cells.
 ...
PMID:In vitro induction of lymphokine-activated killer (LAK) activity in patients with neuroblastoma. 264 3

A wide variety of human cancers currently have no effective treatment and are potential targets for lymphokine-activated killer (LAK) cellular immunotherapy. Relapsed acute lymphocytic leukemia (ALL) and neuroblastoma are two of the major therapeutic challenges in pediatric oncology today. However, one problem which makes LAK immunotherapy in children particularly difficult is obtaining the large numbers of cells required. Present adult therapeutic LAK protocols have utilized short-term (5 day) cultures of interleukin-2 (IL2)-activated cells which are initially obtained from leukopheresis. Since routine use of this procedure in small children is not practical, we have investigated a different approach to obtain increased cell numbers by activation of peripheral blood mononuclear cells with OKT3, a mitogenic anti-CD3 monoclonal antibody, and IL2. Cell growth and LAK activity in OKT3 + IL2-activated cultures were compared to cultures activated with IL2 alone in 2 children with relapsed ALL and 2 children with stage IV neuroblastoma. OKT3 + IL2-activated cultures had marked increases in cell number: after 14 days the OKT3 + IL2-activated cultures yielded an approximately 500-fold increase in cell number compared to a 7-fold increase for cultures activated with IL2 alone. In vitro 51Cr release assays were used to estimate LAK activity of the cultures at 7 and 14 days. When tested against HL60, a natural killer (NK)-resistant tumor cell line, not only were total cytolytic units greatly increased in OKT3 + IL2-stimulated cultures by lytic activity on a per cell basis (lytic units/1 x 10(6) cells) had also markedly increased on day 14 of culture. Phenotypic analysis demonstrated that 80% to 90% of cells in OKT3 + IL2-stimulated cultures were CD3 + T cells. Variable low percentages of CD16 + NK cells were seen in these cultures. In summary, OKT3 + IL2 activation resulted in a large increase in cell yield and the development of high level LAK activity using peripheral blood mononuclear cells from children with cancer. This approach may facilitate the utilization of increased cell numbers in future adoptive immunotherapy protocols, especially in pediatric patients.
 ...
PMID:Augmentation of cell number and LAK activity in peripheral blood mononuclear cells activated with anti-CD3 and interleukin-2. Preliminary results in children with acute lymphocytic leukemia and neuroblastoma. 326 Aug 24

Much effort is devoted to eliminating residual tumor cells - which escape detection by conventional methods - from remission bone marrow harvested for autologous transplantation. The quantitative determination of the efficacy of these purging methods is generally difficult. This report describes an in vitro reproducible tumor model. Normal mononuclear blood cells were deliberately contaminated with cells from the human neuroblastoma cell line SK-N-AS. The frequency of clonogenic SK-N-AS cells was determined in limiting dilution culture before and after treatment. Two methods of purging these tumor cells from the mixed cell suspension were compared, 1) an immunomagnetic method taking advantage of the existence of a monoclonal antibody (mAb) specific for 90-95% of the tumor cells, and 2) a method based on cell mediated cytotoxicity testing the activity of previously lymphokine activated killer (LAK) cells. Immunomagnetic purging eliminated 90% (1 log) of all SK-N-AS cells and 99% (2 log) of the mAb-binding clonogenic tumor cells. In contrast, LAK cell treatment removed only between 0.1 to 0.3 log (23-50%) of the clonogenic SK-N-AS cells.
 ...
PMID:[Quantitative detection and elimination of neuroblastoma cells in vitro. Comparative study of the efficacy of an immunomagnetic method and lymphokine-activated killer cells]. 332 26

Evidence is presented that neuroblastoma tumor cells in host bone marrow is susceptible to autologous lymphokine-activated killer cells (LAK). Thus, immunologic purging of bone marrow with LAK may be considered as a tool in the arsenal of bone marrow purging-for autologous bone marrow transplantation.
 ...
PMID:Lymphokine-activated killer cell lysis of human neuroblastoma cells: a model for purging tumor cells from bone marrow. 333 77

Disialoganglioside GD2 is present on human neuroblastoma and melanoma cells. 3F8 is a murine IgG3 monoclonal antibody specific for GD2, which has shown antitumor effects in patients in preliminary clinical studies. Since antibody mediated cellular cytotoxicity (ADCC) was one of the likely mechanisms producing these observed tumor regressions, the current study was carried out to investigate the activation of ADCC by interleukin-2 (IL-2). ADCC (against human neuroblastoma and melanoma cell lines in vitro) mediated by normal human peripheral blood lymphocytes was increased 100 to 330% after preincubation with IL-2. At limiting concentrations of 3F8 antibody (10 to 100 times less than the amount required by unactivated peripheral blood lymphocytes), activated peripheral blood lymphocytes still mediated efficient ADCC. Activation of ADCC was detected earlier than lymphokine activated killer cell (LAK) activity, required less IL-2 for optimum induction (50 versus 1000 units/ml), and was of equal or greater absolute magnitude (+10 to +200%) against the cell lines tested. ADCC and LAK were independent and additive when measured against the same cell line. The precursor cells for both LAK and activated ADCC bore IgG Fc receptors, but by day 4 of culture with IL-2 much of the LAK activity resided in the Fc negative, Leu11 negative population, and did not mediate ADCC. IL-2 activated ADCC may be of value alone or in conjunction with LAK cells in the therapy of tumors which bind the antibody 3F8.
 ...
PMID:Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. 349 78

Melanomas from different patients have been shown to express shared tumor antigens, which can be recognized in the context of the appropriate MHC class I molecules by cytolytic T cells. To determine if T-cell-defined melanoma antigens are expressed on other tumors of neuroectodermal origin, four melanoma-specific cytotoxic T lymphocyte (CTL) cultures derived from tumor-infiltrating lymphocytes (TIL) were tested for lysis of a panel of 23 HLA-A2+ neuroectodermal tumor cell lines of various histologies, including retinoblastoma (1), neuroblastoma (8), neuroepithelioma (6), astrocytoma (2), neuroglioma (1), and Ewing's sarcoma (5). Low expression of MHC class I and/or ICAM-1 molecules was found on 22 of 23 neuroectodermal tumor lines, and could be enhanced by treatment with interferon gamma (IFN gamma). Following IFN gamma treatment, three Ewing's sarcoma lines were lysed by at least one melanoma TIL culture, and levels of lysis were comparable to melanoma lysis by these TIL. Lysis could be inhibited by monoclonal antibodies directed against MHC class I molecules and against CD3, indicating specific immune recognition of tumor-associated antigens. None of the other neuroectodermal tumors tested were lysed by TIL, but they could be lysed by non-MHC-restricted lymphokine-activated killer cells. This demonstration of immunological cross-reactivity between melanomas and Ewing's sarcomas, two tumors of distinct histological types with a common embryonic origin, has implications for the developmental nature of these CTL-defined tumor antigens. It also raises the possibility that specific antitumor immunotherapies, such as vaccines, may be reactive against more than one form of cancer.
 ...
PMID:Recognition of neuroectodermal tumors by melanoma-specific cytotoxic T lymphocytes: evidence for antigen sharing by tumors derived from the neural crest. 751 27

Human tumor-infiltrating lymphocytes (TIL) were obtained from breast cancer, renal cancer or neuroblastoma to investigate the generation of autologous tumor-reactive CD8+ cytotoxic T lymphocytes (CTL). When TIL were cultured with interleukin (IL)-2 (100 U/ml), the growth of TIL peaked around 8-10 days after the initiation of culture. In contrast, the proliferation of TIL cultured with IL-2 plus IL-12 peaked around 4-5 days after culture and tumor cells rapidly disappeared from the culture. To determine the generation of autologous tumor-reactive CD8+ CTL, TIL-derived CD8+ T cells were separated by FACStar. Both IL-2-activated and IL-2 plus IL-12-activated TIL-CD8+ T cells showed the same level of lymphokine-activated killer activity against a variety of tumor cells. However, TIL-CD8+ T cells activated with IL-2 plus IL-12 revealed greatly augmented cytotoxicity against autologous tumor cells compared with that induced by IL-2 alone. The autologous tumor cell-killing activity of TIL-CD8+ CTL was significantly inhibited by the addition of F(ab)2 anti-CD3 monoclonal antibody, indicating that these CTL recognize autologous tumor antigen through T cell receptor. These results imply that IL-12 is a novel cytokine which facilitates the generation of autologous tumor-reactive CD8+ CTL from TIL.
 ...
PMID:Interleukin-12 augments the generation of autologous tumor-reactive CD8+ cytotoxic T lymphocytes from tumor-infiltrating lymphocytes. 773 Jan 35

Neuroblastoma is the most common extracranial, solid tumor in children. Despite intensive chemotherapy and bone marrow transplantation, the 5-year projected survival rate is 20% to 25%. In vitro studies have shown enhanced natural killer cell (NK) lysis of tumor cells after exposure of NK cells to interleukin-2 (IL-2). In vivo studies have demonstrated similar immunologic effects but have also revealed severe toxicities associated with the use of IL-2. IL-12 is a newly described cytokine that has several properties, including the ability to act synergistically with IL-2 in generating lymphokine-activated killer cells (LAK) against known tumor targets. We investigated the role of IL-12 in the generation of peripheral blood mononuclear cell (PBMC) lysis of neuroblastoma cell lines. PBMC were activated with IL-12 alone and in combination with IL-2. Whereas IL-12 alone produced only modest enhancement of NK cell cytotoxicity, the combination of IL-2 and IL-12 was most effective in activating NK cell lysis of neuroblastoma cell lines. Further, we showed that large granular lymphocytes were the effector cells involved in target cell lysis. Finally, the CD18 molecule was shown to be critical in the lysis of neuroblastoma cells by activated PBMC.
 ...
PMID:Lysis of neuroblastoma cell lines by human natural killer cells activated by interleukin-2 and interleukin-12. 790 63


<< Previous 1 2 3 4 Next >>