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Biomedical subjects

N K Cheung

Publications and source records attributed to N K Cheung.

At least 127 records · Page 7Linked to original sources
PubMed1991

Radioimmunodetection of neuroblastoma with iodine-131-3F8: correlation with biopsy, iodine-131-metaiodobenzylguanidine and standard diagnostic modalities.

Iodine-131-3F8, a murine IgG3 monoclonal antibody specific for ganglioside GD2 was evaluated by radioimmunoscintigraphy in 42 patients with neuroblastoma. Comparison was made with 131I-metaiodobenzylguanidine (MIBG), 99mTc-methylene diphosphonate (MDP) bone scans, as well as computed axial tomography (CT) or magnetic resonance imaging (MRI). Iodine-131-3F8 detected more abnormal sites (283) than [131I] MIBG (138) or 99mTc-MDP (69), especially in patients with extensive disease. In 20 patients with soft-tissue tumors demonstrated by CT/MRI, 131I-3F8 detected the disease in 18. Upon surgical resection, two tumors interpreted as negative with 131I-3F8 imaging revealed ganglioneuroma, one showing microscopic foci of neuroblastoma. In contrast, 131I-3F8 imaging identified tumors that were confirmed histologically as neuroblastomas. In 26 patients with evidence of marrow disease by antibody scans, 14/26 had confirmation by iliac crest marrow aspirate/biopsy examinations. We conclude that 131I-3F8 scintigraphy has clinical utility in the management of patients with neuroblastoma by improving the sensitivity of tumor detection.

3-Iodobenzylguanidine↗
PubMed1990

Dose-intensive use of cyclophosphamide in ablation of neuroblastoma.

A dose-intensive, cyclophosphamide (CPM)-based chemotherapy regimen was tested in 22 children with newly diagnosed metastatic or refractory neuroblastoma. The N5 protocol consisted of four courses of CPM (140 mg/kg over 2 days), doxorubicin (45 mg/m2 over 3 days), and vincristine (0.05 mg/kg/d on days 1, 2, and 9) (CAV regimen), followed by three courses of cisplatin (40 mg/m2/d) and VP16 (150 mg/m2/d) for 3 days (PVP regimen). Courses started when the neutrophil count was 500/microliters or greater and the platelet count was greater than 100,000/microliters; most courses began by day 21. Extramedullary toxicities were mild. All patients had Grade 3 to 4 myelosuppression, yet bone marrow harvested after the N5 protocol engrafted in 11 of 11 patients whose post-N5 treatments required autologous bone marrow transplantation (ABMT). Among 14 previously untreated patients, the N5 plus surgery achieved 9 complete remissions (CR) or very good partial remissions (VGPR) and 3 partial remissions (PR). An additional patient achieved CR with CAV, but experienced a recurrence in the bone marrow after PVP. The sole previously untreated patient whose bone marrow disease did not resolve received courses of the N5 at prolonged intervals (for nonmedical reasons). Among eight patients with progressive (six patients) or refractory (two patients) disease while on other, lower dose regimens, the N5 plus surgery achieved five CR/VGPR, two PR, and one minor response (MR). In conclusion, dose-intensive use of CPM has tolerable toxicity and does not preclude autografting; when administered in conjunction with other cytotoxic agents, it is highly effective against metastatic neuroblastoma and causes regressions of disease resistant to less intensive regimens. This approach plus surgery reliably achieves a minimal disease state that may be amenable to definitive ablation with relatively nontoxic therapies.

Adolescent↗
PubMed1990

Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2.

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.

Antibodies, Monoclonal↗
PubMed1990

Phagocytosis of tumor cells by human monocytes cultured in recombinant macrophage colony-stimulating factor.

Macrophages and cultured human monocytes can mediate efficient antibody-dependent cytotoxicity (ADCC) against human tumor cells using monoclonal antibodies (mAbs). The mechanism of this killing is usually assumed to involve secreted factors (reactive oxygen intermediates, tumor necrosis factor, or other cytotoxic factors) leading to target cell lysis. In this study, we present evidence that phagocytosis of intact target cells is the principal mechanism of antitumor cytotoxicity in our in vitro model of ADCC by cultured monocytes. Human monocytes cultured in recombinant human macrophage colony-stimulating factor ingested up to 100% of fluorochrome-labeled melanoma and neuroblastoma target cells, in the presence of an appropriate antitumor mAb. Electron microscopy demonstrated phagocytosis of intact tumor cells by cultured monocytes during ADCC. All of the radionuclide in radiolabeled target cells was taken up by monocytes during phagocytosis. By preventing the release of radioisotope tracers, phagocytosis thus prevents the detection of this very efficient form of cytotoxicity by most conventional assays.

Antibodies, Monoclonal↗
PubMed1990

Effects of parenteral recombinant human macrophage colony-stimulating factor on monocyte number, phenotype, and antitumor cytotoxicity in nonhuman primates.

Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF.

Animals↗
PubMed1990

Autografting with bone marrow exposed to multiple courses of very high dose cyclophosphamide in vivo and to 4-hydroperoxycyclophosphamide in vitro.

Intensive chemotherapy prior to harvesting autologous bone marrow may be advantageous for cancers that infiltrate the bone marrow. This approach, however, may deplete hemopoietic reserves or damage the hemopoietic microenvironment and thereby jeopardize posttransplant engraftment; in vitro treatment of bone marrow to ensure a tumor-free state may enhance the risk of nonengraftment. We addressed these concerns in a pilot study of patients with disseminated neuroblastoma. Bone marrow was harvested after initial intensive therapy that included 1) three to six courses of very high dose cyclophosphamide (CPM) (100-140 mg/kg in five patients, 140-160 mg/kg in nine patients), plus doxorubicin and vincristine, followed by 2) a median of three strongly myelosuppressive courses of cisplatin/VP16. The median interval between courses was 23 days. The marrow was treated in vitro with the CPM congener 4-hydroperoxycyclophosphamide (4-HC) and cryopreserved. It was infused after a massive cytoreduction regimen of melphalan 180 mg/m2 (n = 7) or thiotepa 900 mg/m2 (n = 7), plus cisplatin, BCNU, VP16, and local radiation. All 14 patients reconstituted hemopoiesis (median of 37 days to neutrophils greater than or equal to 500/microliter and of 63 days to platelets greater than 50,000/microliters). The number per kilogram body weight of hemopoietic progenitor cells (CFU-GM, BFU-E) in the autografts correlated significantly with the rate of hematologic recovery. Preharvest CPM dosage, however, did not. The use of thiotepa, as opposed to melphalan, was associated with a significantly slower posttransplant platelet recovery, suggesting a possible adverse effect of high-dose thiotepa on posttransplant hemopoiesis. In sum, while reinforcing evidence of a stem cell sparing effect of CPM, this pilot study more importantly delineates the degree to which high-dose alkylator therapy can be exploited to attain maximal dose intensity beginning at diagnosis. This aggressive treatment approach may have wide applicability, since CPM is among the most active agents against a spectrum of pediatric cancers.

Adolescent↗
PubMed1990

Complement killing of human neuroblastoma cells: a cytotoxic monoclonal antibody and its F(ab')2-cobra venom factor conjugate are equally cytotoxic.

Only a few monoclonal antibodies mediate complement lysis of tumor cells, but for several antibodies it has been demonstrated that a complement-activating function can be introduced by covalent coupling of cobra venom factor (CVF), a non-toxic glycoprotein which is a structural and functional homologue of human complement component C3. In this study we compared the efficacy of complement killing of human neuroblastoma cells by the complement-activating monoclonal antibody 3F8 directed against the GD2 ganglioside antigen with that of its F(ab')2-CVF conjugate. At equal numbers bound per cell the 3F8 antibody and the 3F8 F(ab')2-CVF conjugate were found to be equally cytotoxic in the presence of complement from several species including human. Maximal killing reached up to 98%. The kinetics of killing and the bivalent metal requirement confirmed that the cytotoxic activity of the 3F8 antibody is mediated via the classical pathway and that of the 3F8 F(ab')2-CVF conjugate via the alternative pathway. To achieve a comparable degree of killing, an approximately eight-fold higher concentration of the 3F8 F(ab')2-CVF conjugate was required which appears to be a consequence of the approximately eight-fold lower binding activity of the 3F8 F(ab')2-CVF conjugate compared to the intact 3F8 antibody. Our data suggest that the coupling of CVF to non-cytotoxic antibodies allows the generation of conjugates with a cytotoxic activity similar to that of inherently cytotoxic antibodies.

Antibodies, Monoclonal↗
PubMed1989

Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. Induction of efficient antibody-mediated antitumor cytotoxicity not detected by isotope release assays.

Macrophage colony-stimulating factor (M-CSF) is known to stimulate proliferation of monocyte/macrophage progenitors and enhance in vitro antitumor cytotoxicity by murine macrophages. In this paper we have shown that recombinant human M-CSF causes human peripheral blood monocytes to differentiate in culture into metabolically active macrophage-like cells. These cells mediate very efficient antibody-dependent cellular cytotoxicity (ADCC) against human melanoma and neuroblastoma cell lines in the presence of two murine IgG3 mAbs (3F8 and R24). They also mediate antibody-independent cytotoxicity (or cytostasis) to a lesser extent. Human serum had an inconsistent effect on ADCC, but often induced similar high levels of ADCC. Cytotoxicity was measured using a novel ELISA to detect surviving tumor cells after ADCC. Two conventional isotope-release assays (51Cr and [3H]TdR) underestimated or entirely failed to detect ADCC by M-CSF-activated monocytes. Optimal activation occurred with 100-300 U/ml of M-CSF, and required 9-11 d for completion. Most of the M-CSF cultured monocytes expressed the low-affinity Fc receptor (CD16). ADCC by cells of the monocyte/macrophage lineage using murine IgG3 mAbs may have significance for the immunotherapy of human malignancies.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1989

GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma.

3F8 is a murine monoclonal IgG3 antibody specific for the tumor-associated antigen ganglioside GD2. Previous in vitro studies suggest that tumor regressions observed in a phase I clinical trial of 3F8 may be attributable to complement activation by 3F8 and to 3F8-dependent cellular cytotoxicity (ADCC) with lymphocytes. We now describe 3F8-mediated ADCC of GD2-positive tumor targets (melanoma and neuroblastoma) with human granulocytes and report that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced this phenomenon. Cytotoxicity required binding of 3F8 to the low-affinity Fc receptor type III (CD16) on the granulocytes and was poor with tumor-binding monoclonal antibodies of other immunoglobulin (ie, non-IgG3) subclasses. GM-CSF (2 to 20 ng/mL) increased ADCC by 93% to 267% at limiting dilutions of 3F8 (1 microgram/mL). With most GD2-positive cell lines tested, this effect translated into a tenfold or greater augmentation in 3F8 efficiency at mediating ADCC. Comparable enhancement occurred whether GM-CSF was present in the ADCC assay or granulocytes were incubated with GM-CSF and washed before the assay. Nonoxidative mechanisms may be important for ADCC since 3F8 mediated ADCC with granulocytes from two children with chronic granulomatous disease; this cytotoxicity was also enhanced by GM-CSF. Since GM-CSF induces a neutrophilia in patients, our data suggest that this cytokine may have the potential of amplifying 3F8 antitumor activity in patients by increasing effector cell numbers and by priming granulocytes for greater cytotoxicity.

Adjuvants, Immunologic↗
PubMed1989

Comparison of radiolabeled monoclonal antibody and magnetic resonance imaging in the detection of metastatic neuroblastoma in bone marrow: preliminary results.

Magnetic resonance imaging (MRI) was compared with iodine-131-labeled monoclonal antibody scanning for ability to detect bone marrow metastases in the spine, pelvis, and femurs of children with disseminated neuroblastoma. The five patients in this study had received high-dose chemotherapy and radiation, either with (N = 2) or without (N = 3) bone marrow transplants. MRI disclosed marrow abnormalities at all sites detected with the radiolabeled antibody, which is highly specific for neuroblastoma. However, several diffuse and multifocal marrow changes apparent on MR scans were not present on scintigrams, indicating that MRI is probably less specific than monoclonal antibody imaging. Both methods were more useful than conventional radiography, computed tomography, and 99mTc-MDP bone scans for identifying sites of marrow involvement by neuroblastoma.

Antibodies, Monoclonal↗
PubMed1989

Monoclonal antibody 3F8 recognises the neural cell adhesion molecule (NCAM) in addition to the ganglioside GD2.

The monoclonal antibody 3F8 has been described as binding to the ganglioside GD2. This antibody, of the IgG3 isotype, has been used in immunotherapy, radioimmunolocalisation and targeted radiation therapy. 3F8 was originally observed to have a binding profile similar to two monoclonal antibodies, UJ13A and 5.1.H11, characterised as binding to the neural cell adhesion molecule (NCAM). This observation has also been confirmed using a hetero-antiserum prepared against purified NCAM. The cross-reactivity of 3F8 with NCAM has been confirmed by cross-blocking studies with an anti-NCAM antiserum, and by direct immunoprecipitation and gel electrophoresis. In addition, we show that 3F8 binds to human NCAM from 3T3 fibroblasts transfected with NCAM cDNA constructs. It is possible that the common epitope shared by GD2 ganglioside and NCAM involves sialic acid residues common to both the ganglioside and the glycoprotein.

Adult↗