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)

We were interested in evaluating immune function in very young children with cancer who were treated with gamma-interferon on a sequential basis. Though gamma-interferon was reportedly able to enhance NK activity, and while many tumor cells are susceptible to lysis by these cells, this effector mechanism is not fully developed in very young children. Since LAK cells also have anti-tumor activity and are produced in response to stimulation with Interleukin-2, we investigated whether LAK killing might be more readily demonstrable in very young children. We report that LAK activity in this group did not differ significantly from that of adults. This was also true for a small group of neuroblastoma patients tested. Furthermore, as opposed to NK activity, LAK activity was demonstrable following freezing and thawing of PBL.
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PMID:The development of cell mediated immunity: very young children have strong LAK activity. 196 85

The role of Interferon-gamma (IFN-gamma) in the immunotherapy of neuroblastoma was investigated. In vitro experiments showed that IFN-gamma augments the cytotoxicity of Natural Killer (NK) cells and of interleukin 2 (IL-2)-activated NK (LAK) cells against neuroblastoma target cells. Incubation of the neuroblastoma cells with IFN-gamma resulted in an increased susceptibility of these target cells to NK and LAK cells. Additionally, the IFN-gamma-treated neuroblastoma cells showed an increased susceptibility to the antibody-dependent cellular cytotoxicity (ADCC). In patients who have been treated with continuous infusions of IL-2, IL-2-induced secretion of IFN-gamma was detected by measuring the elevation of the 2-5 A synthetase activity in peripheral mononuclear cells or the 2-5 A oligoadenylates in the serum, although IFN-gamma itself was not detectable. From these results we conclude that IFN-gamma may play an important role in the immunotherapy of neuroblastoma in combination with IL-2 and/or with monoclonal antibodies.
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PMID:[The role of interferons in neuroblastoma. 2: Immunomodulatory effects]. 211 81

Forty-seven patients with renal carcinoma were included in first line or rescue protocols of immunotherapy including IL2 alone or in association with LAK cells, INF alpha or TNF. The toxicity was mild and the mortality was 2% (1 patient). The response rate was 26%. Nineteen children with neuroblastoma received IL2 either alone or in combination with LAK cells. The morbidity and mortality were higher in patients with end stage disease who had previously received high dose and prolonged chemotherapy. In contrast, the toxicity was mild and transient in patients treated in the months following autologous bone marrow transplantation. The only complete response observed was in 1 child treated with IL2, 4 months after high dose chemotherapy and ABMT. Immunological analysis showed that the immunomodulatory effect of IL2 is very different depending on whether IL2 is used alone or in combination with other cytokines; moreover, the biological effect of IL2 is dependent on the immunological status of the patients prior to IL2 therapy.
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PMID:[Adoptive immunotherapy with interleukin 2 in oncology]. 222 65

The susceptibility of neuroblastoma cells to cytotoxic T lymphocyte (CTL)-mediated killing was investigated. Cytotoxic lines were generated by sensitizing peripheral blood lymphocytes against two stimulator cells, a neuroblastoma line, CHP-100, and normal allogeneic lymphocytes, LS. LS cells shared class I antigens with CHP-100, but in addition expressed class II antigens. The resulting cell lines strongly lysed both CHP-100 and LS cells, but poorly killed the natural killer (NK) target K562. Specific blocking of lysis by a monoclonal antibody directed against class I determinants and strong killing by the line following depletion of cells with NK or LAK markers demonstrated that this neuroblastoma line was lysed by CTL.
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PMID:Susceptibility of human neuroblastoma cell lines to cytotoxic T lymphocyte-mediated lysis. 236 16

Nine children with poor prognosis neuroblastoma have been treated by continuous infusion of IL-2 and autologous LAK cells, as described previously by West et al. in adult patients. Six patients were in relapse after high-dose chemotherapy and autologous BMT and three presented with primary refractory disease after conventional therapy. Although patients were very young (median age 6 years; average weight 17 kg), infusion of IL-2, cytapheresis and reinjection of LAK cells appeared feasible with the usual and transient complications observed with IL-2. Haematological toxicity, although reversible, was more important than usually described and due to the presence of bone-marrow metastases in 8 of the 9 patients. Life-threatening toxicity was observed in only one of the admission centres and was probably due to the rapid reinjection of a very large number of activated cells. Two patients presenting with very active disease after high-dose chemotherapy and autologous or allogeneic BMT received IL-2 alone, at 120 days and at 90 days after the graft. The reactivation of grade-II GVHD was the major complication in the patient treated after an allograft, whereas no BMT-related toxicity was observed in the patient treated after the autologous BMT. Immunological modifications induced by IL-2 were very different between these patients. As expected, a preferential outgrowth of NK cells with both NK and LAK activity was observed in the patient treated just after the autograft. In contrast, in the patient treated after an allograft and in the 9 patients in relapse, T lymphocytes remained the major mononuclear cell population with a very large excess of CD8+ T cells. All patients progressed after the first induction cycle with the exception of the only patient treated after autologous BMT who reached a very good partial remission with disappearance of the local tumor and bone metastases. Although very preliminary, these data clearly show that the efficacy of IL-2 largely depends on the patient's immunological status with the optimal effect being observed when IL-2 is given in the first few months following an autograft.
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PMID:A phase-II study of adoptive immunotherapy with continuous infusion of interleukin-2 in children with advanced neuroblastoma. A report on 11 cases. 267 Feb 9

Expansion of the natural killer (NK) subset of lymphocytes represents a rare leukemia phenotype with variations in clinical presentation, morphology, surface phenotype, and effector function. This paper reports on a 5-year-old male patient who had an unusual presentation of an NK cell leukemia that was initially diagnosed as neuroblastoma. A bone marrow (BM) aspirate showed clumps of undifferentiated cells with the following phenotype: CD56bright+, CD33dim+, CD45-, CD2-, CD19-, CD16-, and CD57-. Cytochemistry was noncontributory. The patient, having failed to respond to conventional neuroblastoma chemotherapy, was subsequently diagnosed as having NK cell leukemia based on functional in vitro assays. The patient responded to acute lymphoblastic leukemia (ALL) chemotherapy but relapsed 4 weeks into treatment and eventually died 25 weeks after initial presentation. The cell surface phenotype observed is consistent with a rare NK cell subset, the biology of which has not been well defined. Freshly isolated BM cells killed K562 cells in a conventional 51Cr-release assay. Both interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) induced LAK activity against the Daudi cell line. IL-2 induced proliferation of the leukemic cells. TNF-alpha, IFN-gamma, IL-6, IL-1ra, and TGF-beta levels were assessed and found to be concentrated in BM, in contrast to plasma samples. TNF-alpha was present at a high concentration in BM (150.9 pg/ml), probably a reflection of the associated disease pathology of severe bone pain and pyrexia. In summary, this paper details clinical and laboratory investigations of a leukemia of a rare NK cell subset.
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PMID:Recognition of unusual presentation of natural killer cell leukemia. 757 92

We determined the expression of intercellular adhesion molecules (ICAM) on neuro-2a cells in order to evaluate whether they were involved in cytolysis of murine neuroblastoma. Fluorescence-activated cell sorting analysis revealed that the control neomycin-resistance-gene-transduced line (neuro-2a/LN) had poor expression of ICAM-1 (mean channel fluorescence, MCF = 3.7). An ICAM-1-positive transfectant of neuro-2a (neuro-2a/ICAM-1+) (MCF = 64.3) was generated to evaluate directly the role of this adhesion molecule in cytolysis. Neuro-2a/ICAM-1+ was more sensitive to LAK killing (69.7% at an effector-to-target ratio of 100:1) compared to neuro-2a/LN (48.6%) (P < 0.001). Blocking of neuro-2a/LN and neuro-2a/ICAM-1+ lysis with anti-ICAM-1 monoclonal antibodies (mAbs) did not account for all the LFA-1-dependent killing. These data indicate that even in neuro-2a/ICAM-1+ cells, other LFA-1 ligands participated in the effector-target interaction. Therefore, we examined these cell lines for ICAM-2 expression. Both neuro-2a/LN and neuro-2a/ICAM-1+ lines expressed ICAM-2 (MCF = 16.4 and 16.5). ICAM-2 accounted for the majority of the LFA-1-dependent killing in the ICAM-1-negative target, neuro-2a/LN, while ICAM-1 played a primary role in the cytolysis of the ICAM-1+ transfectant. Inhibition of lysis in the presence of anti-ICAM-1 and ICAM-2 mAbs was comparable to that seen with the addition of anti-LFA-1 mAb, indicating that other LFA-1 ligands were not involved in this system. ICAM-1 expression was associated with decreased in vivo tumorigenicity, mice inoculated with neuro-2a/ICAM-1+ cells had a significantly longer survival compared to those receiving neuro-2a/LN cells (median survival time 35.5 versus 24.5 days) (P < 0.001). It is important to note that ICAM-1 transfection of murine neuroblastoma did not alter its metastatic potential. We conclude that transfection of mouse neuroblastoma with ICAM-1 increases its sensitivity to in vitro lysis and reduces its in vivo tumorigenicity. In ICAM-1-negative murine neuroblastoma cells, ICAM-2 plays a primary role in cell-mediated lysis.
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PMID:Transfection of the mouse ICAM-1 gene into murine neuroblastoma enhances susceptibility to lysis, reduces in vivo tumorigenicity and decreases ICAM-2-dependent killing. 790 90

We have established a new human neuroblastoma (NB) cell line from the bone marrow of a 1-year-old boy with NB, termed JK-NB1, which showed constant growth for as long as 17 months or more, similar phenotype to those of other reported NB cell lines, colony formation in liquid and methylcellulose culture, N-myc amplification, high expression of N-CAM, and NSE production. We have tried to induce LAK cell activity with peripheral blood mononuclear cells (PBMCs) from the patient against the autochthonous JK-NB cells. PBMCs from the patient proliferated up to 20-fold in the presence of interleukin-2 (IL-2) after 9 days of incubation, and LAK activity increased up to 24.7-fold and killed all of the JK-NB1 cells. In contrast, IL-2 alone or PBMCs from the patient or a healthy adult donor had little effect on the growth of NB cells. These data suggest that it is possible to induce LAK cell activity in PBMCs from the patient against autologous as well as allogenic NB cells, and provide a rational base for the clinical use of IL-2 as one of the treatments for NB.
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PMID:Establishment of a neuroblastoma cell line and induction of lymphokine-activated killer (LAK) activity against the autologous neuroblastoma cell line. 814 11

Widely disseminated neuroblastoma in children older than infancy remains a very poor prognosis disease. Even the introduction of marrow ablative chemotherapy with autologous rescue has not significantly improved the outlook for these children, presumably because of a failure to eradicate minimal residual disease. One additional approach which may hold promise is the use of immunomodulation with cytokines such as IL2 in the setting of minimal residual disease (MDR), for example after intensive chemotherapy and ABMT. However, considerable variability in the susceptibility of neuroblastoma cells to natural killer (NK) and lymphokine-activated (LAK) killing has been observed, and it is presently unclear how NK and LAK cells recognise neuroblastoma cells. In this paper we examine expression of cell adhesion molecules on neuroblastoma to determine which of these modify interaction with NK and LAK cells. We find that LFA-3 (CD58), the ligand for CD2 is of predominant importance in predicting susceptibility of neuroblastoma to the cytotoxic actions of NK and LAK cells, while expression of ICAM-1 (CD54) may also modify susceptibility. These findings were confirmed by blocking experiments in which co-culture of target cells with ICAM-1 and LFA-3 reduced LAK and NK cytotoxicity. Study of the immunophenotypic features of each patient's neuroblastoma cells before induction of MRD may be valuable in determining the likely effect of IL2 in predicting disease reactivation.
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PMID:Mechanisms of selective killing of neuroblastoma cells by natural killer cells and lymphokine activated killer cells. Potential for residual disease eradication. 849 26

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


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