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N K Cheung

Publications and source records attributed to N K Cheung.

At least 91 records · Page 5Linked to original sources
PubMed1996

Prognostic value of TrkA protein detection by monoclonal antibody 5C3 in neuroblastoma.

The effects of nerve growth factor, a neurotrophin mediating growth and differentiation of neural crest-derived cells, are mediated by the receptor TrkA. TrkA mRNA expression has been associated with a good prognosis in human neuroblastoma (NB). We describe the use of monoclonal antibody 5C3 in detecting TrkA expression by immunohistochemistry in NB and other malignant tumors. A murine anti-TrkA IgG1 monoclonal antibody, 5C3, was generated against the extracellular domain of human p140(TrkA). 5C3 detected a 140-kDa band on Western blots. 5C3 was optimized for immunostaining and used to detect p140(TrkA) on 113 frozen NB samples and 42 samples from nine other malignancies. MOPC21 IgG1 antibody was used as a control. Results by immunohistochemistry were compared to TrkA expression assessed by reverse transcription-PCR and Western analysis. The prognostic value of TrkA expression by these methods was evaluated and compared to other known prognostic variables, including stage, age, and MYCN copy number. TrkA expression was detected by immunohistochemistry in 73 of the 113 NB tumor specimens and strongly correlated with nonmetastatic disease. TrkA expression was specific for NB among small round blue cell tumors. Both TrkA expression by immunohistochemistry and localized/4s disease correlated with survival. Tumors from 55 of 60 patients with localized/4s NB exhibited homogeneous or a mixed pattern of TrkA immunohistochemistry, whereas only 18 of 53 patients with stage 4 NB were immunoreactive. Detection of TrkA by reverse transcription-PCR and Western analysis was much more sensitive and no longer correlated with survival. 5C3 enables rapid detection of p140(TrkA) by immuno-histochemistry and identifies patients more likely to have localized NB with a favorable clinical outcome. Lack of TrkA expression is correlated with metastatic, malignant NB. A subset of patients with NB, however, died of aggressive metastatic disease despite TrkA expression. As a mimic of nerve growth factor, 5C3 may be useful in the study of TrkA-expressing tumors.

Antibodies, Monoclonal↗
PubMed1995

GD2 oligosaccharide: target for cytotoxic T lymphocytes.

Carbohydrate antigens rarely provide target epitopes for cytotoxic T lymphocytes (CTL). Disialoganglioside GD2 is a glycolipid expressed at high levels in human tumors and a small group of murine lymphomas (EL4, RBL5, RMA, RMA-S, A13, and BALBRVE). Immunization of C57B1/6 mice with irradiated EL4 cells stimulated a specific CTL response and protected these animals from engraftment of EL4 lymphoma. The CTL activity resided in the CD4-CD8+ population, was dependent on T cell receptor alpha/beta, and was not removed by anti-natural killer cell immunoabsorption, but was restricted to GD2 and H-2b bearing targets. CTL activity could be completely inhibited by GD2-oligosaccharide-specific monoclonal antibodies and their F(ab')2 fragments, but not by immunoglobulin G3 myelomas or antibodies against GD3 or GM2. Soluble GD2 did not inhibit specific tumor lysis. RMA-S lymphoma cells (GD2+H-2b-TAP2 deficient) were resistant to GD2-specific CTL. Sialic acid-containing peptides eluted from EL4 lymphoma cells could (a) stabilize H-2 molecules on RMA-S cells and (b) sensitize them for GD2-specific CTL. Control peptides (derived from vesicular stomatitis virus nucleoprotein peptide and GD2-negative lymphomas) could also stabilize H-2 on RMA-S, but were resistant to GD2-specific CTL. These H-2-binding peptides could be purified by anti-GD2 affinity chromatography. We postulate a new class of naturally occurring epitopes for T cells where branched-chain oligosaccharides are linked to peptides with anchoring motifs for the major histocompatibility complex class I pocket. While analogous to the haptens trinitrophenyl and O-beta-linked acetyl-glucosamine, the potential implications of natural carbohydrates as antigenic epitopes for CTL in biology are considerable.

Animals↗
PubMed1995

Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer.

BACKGROUND: Patients with neuroendocrine-related tumors and paraneoplastic encephalomyelitis (PEM) or paraneoplastic sensory neuronopathy (PSN) develop high titers of antibodies, called anti-Hu, against neuronal proteins expressed in their tumors, usually small cell lung cancer (SCLC). These tumors appear to be more indolent than those not associated with anti-Hu antibodies. The aims of this study were to determine 1) if patients with neuroblastoma (NB) also have anti-Hu antibodies, 2) the correlation between antibody titer and survival, and 3) if coexpression of Hu antigens and major histocompatibility proteins (MHC) by the tumor correlates with the development of anti-Hu associated PEM/PSN: METHODS: Using immunohistochemistry and Western blot analysis, the sera of 109 patients with NB whose neurologic condition was concealed at the time of the study were examined for the presence of anti-Hu antibodies. The expression of Hu antigens and MHC proteins in 50 nonselected NB and 26 SCLC (16 known to be from seropositive and 10 from seronegative patients) was examined using immunohistochemistry. RESULTS: Four Stage 4 NB patients were seropositive and had longer survival (median 86 months) than 71 seronegative patients in the same age group and with the same tumor stage (median survival, 28.5 months). Seventy-eight percent of NB and all SCLC expressed Hu antigens. Overall, 17 of 20 tumors from seropositive patients expressed both Hu and MHC Class I proteins, but only 4 of 30 tumors from seronegative patients expressed both proteins (P < 0.0001). CONCLUSIONS: 1) Some patients with NB develop anti-Hu antibodies; a search for that type of tumor is indicated in seropositive children, 2) most NBs and SCLCs express Hu antigens but only a few are associated with anti-Hu antibodies, and 3) Class I MHC expressed by some Hu antigen-bearing tumors may play a role in the development of anti-Hu associated PEM/PSN:

Adult↗
PubMed1995

Quantitative studies of monoclonal antibody targeting to disialoganglioside GD2 in human brain tumors.

Iodine-131 3F8, a murine IgG3 monoclonal antibody that targets to GD2-bearing tumors, was administered intravenously to 12 patients with brain tumors. Six patients received 2 mCi (0.74 Bq) of 131I-3F8, five patients 10 mCi (3.7 Bq)/1.73 m2 of 131I-3F8, and one patient 2.6 mCi (0.96 Bq) of 124I-3F8, with no side-effects. Nine of 11 malignant gliomas and the single metastatic melanoma showed antibody localization, with the best tumor delineation on single-photon emission tomography (SPET) following 10 mCi (3.7 Bq)/1.73 m2 dose. No nonspecific uptake in the normal craniospinal axis was detected. There was no difference in the pharmacokinetics of low-dose versus the higher-dose antibody groups; plasma and total-body half-lives were 18 h and 49 h, respectively. Surgical sampling and time-activity curves based on quantitative imaging showed peak uptake in high-grade glioma at 39 h, with a half-life of 62 h. Tumor uptake at time of surgery averaged 3.5 x 10(-3) %ID/g and peak activity by the conjugate view method averaged 9.2 x 10(-3) %ID/g (3.5-17.8). Mean radiation absorption dose was 3.9 rad per mCi injected (range 0.7-9.6) or 10.5 cGy/Bq (range 1.9-26). There was agreement on positive sites when immunoscintigraphy was compared with technetium-99m glucoheptonate/diethylene triamine penta-acetic acid planar imaging, thallium-201 SPET, and fluorine-18 fluorodeoxyglucose positron emission tomography. Taken together, these data suggest that quantitative estimates of antibody targeting to intracranial tumors can be made using the modified conjugate view method.

Adolescent↗
PubMed1995

Antibody-independent phagocytosis of tumor cells by human monocyte-derived macrophages cultured in recombinant macrophage colony-stimulating factor.

Human monocytes exposed in vitro to recombinant macrophage-colony-stimulating factor (rhMCSF) differentiate into monocyte-derived macrophages (MDM), which mediate efficient antibody-dependent cytotoxicity (ADCC) against tumor cells. We and others have shown that this form of ADCC is unusual in that phagocytosis, rather than extracellular lysis, appears to play the major role in target cell killing. In this study, we asked whether the phagocytic form of cytotoxicity seen with ADCC could occur in the absence of an opsonizing antibody. We now report that, whereas cell lines derived from solid tumors are often resistant to antibody-independent cytotoxicity, malignant cells of lymphoid origin appear particularly susceptible to such antibody-independent killing. We found that all of nine lymphocytic leukemia and lymphoma cell lines tested in a total of 35 experiments, plus all four samples of fresh leukemic blasts, were consistently susceptible to antibody-independent MDM cytotoxicity. Antibody-independent cytotoxicity against these cells was efficient (40%-63% killing) at effector: target (E:T) ratios as low as 2:1. Like ADCC, antibody-independent cytotoxicity involved phagocytosis of target cells, as demonstrated by ingestion of fluorescently labeled targets and analysis by flow cytometry. At the time of phagocytosis, the majority of target cells retained membrane integrity, as indicated by the direct transfer of intracellular [51Cr]chromate from radiolabeled targets to phagocytosing MDM, without release of the label into the medium. However, in contrast to ADCC, we found that the degree of antibody-independent cytotoxicity was not a function of the E:T ratio. Instead, a constant proportion of the available target cells were killed regardless of the E:T ratio, suggesting that target cell recognition, rather than effector cell potency, might be the limiting factor in determining cytotoxicity. In additional experiments, we have also identified a second tumor cell type, nueroblastoma, as being susceptible to antibody-independent phagocytosis (all of five cell lines tested, cytotoxicity 40%-93%, E:T = 3:1). Our data thus indicate that the cytotoxicity induced by rhMCSF is not confined to antibody-mediated killing, and that phagocytosis can play a significant role in target cell destruction even in the absence of opsonizing antibody.

Humans↗
PubMed1994

Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival.

Clinical strategies which modulate the human anti-mouse antibody response (HAMA) in patients may have a profound influence on the idiotype network inducible by murine monoclonal antibodies (MoAb). Prior to myeloablative chemotherapy (ABMT), 9 patients with Stage IV neuroblastoma were imaged with 131I-3F8, a MoAb specific for the ganglioside GD2. Their serum HAMA, anti-idiotypic, anti-GD2, and anti-anti-idiotypic antibodies were assayed by enzyme-linked immunosorbent assay prior to, and at 3 and 6 months postimaging. HAMA and anti-idiotypic levels remained low, in contrast to the high levels in 10 patients imaged with 131I-3F8 without ABMT. Five of the 9 patients are long-term survivors; all had elevated anti-GD2 and anti-anti-idiotypic levels, significantly higher than those who died of disease. Although 131I-3F8 imaging prior to ABMT detected abnormal sites in 4 of 9 patients, 3 of the 4 patients have continued in remission for 24-63 months after ABMT, and all 3 mounted anti-GD2 and anti-anti-idiotypic antibody responses. We conclude that myeloablative therapy strongly suppressed the HAMA/anti-idiotypic response to murine MoAb and that the prognostic significance of host immune response to ganglioside GD2 MoAb deserves further investigation.

Animals↗
PubMed1994

Stage 4 neuroblastoma diagnosed at more than 1 year of age: gross total resection and clinical outcome.

The importance of gross total resection of the primary tumor in stage 4 neuroblastoma is controversial. The purpose of this study was to assess the impact of gross total resection of the primary tumor on clinical outcome in patients with stage 4 neuroblastoma diagnosed at more than 1 year of age. The authors retrospectively analyzed 70 newly diagnosed cases treated with one of five regimens of increasing dose-intensity. Outcome variables included survival time from diagnosis, and time to local recurrence or local tumor progression. Patient variables analyzed for impact on survival included age, anatomic location of the primary tumor, radiation treatment of the primary site, complete resection at diagnosis, gross total resection (GTR) at any time in the course of therapy, and treatment protocol dose-intensity. GTR was accomplished in seven patients at the time of diagnosis and in 32 patients after chemotherapy. The likelihood of complete gross resection after chemotherapy increased with greater protocol intensity. The only patient variables that correlated with improved survival were GTR (P = .03) and chemotherapy protocol (P = .01). GTR was also associated with improved local control. Although an independent effect of GTR on survival was not demonstrable because complete resection after chemotherapy correlated strongly with increasing protocol intensity, its association with improved overall survival was striking. These results support a continued role for GTR in high-risk neuroblastoma, along with intensive chemotherapy.

Adolescent↗
PubMed1994

Current status of radioimmunotherapy.

Radioimmunotherapy with radiolabeled monoclonal antibodies is increasingly effective for hematopoietic tumors, with a number of investigators reporting persistent major responses. Radioimmunotherapy for solid tumors has been more difficult and only an occasional major response has been reported and these have so far not been persistent. Toxicity is predominantly hematopoietic, with platelets being most sensitive to the effects of radiation. Even at ultra-high doses (up to 28 mCi/kg of 131I), second organ toxicity has not been reached. Rational approaches to dose planning are becoming possible with improvements in dosimetry, based on quantitative SPECT and PET imaging. Current therapeutic indices for tumor/marrow, the most radiosensitive organ, are in the range of 5-10 to 1. This is probably still too low for curative treatment of solid tumors, and further refinements, perhaps based on novel antibody formulations, are needed.

Clinical Trials as Topic↗
PubMed1994

Oral calcium treatment in vitamin D-dependent rickets type II.

Vitamin D-dependent rickets type II is a rare hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D3. There is a great heterogeneity in the clinical presentation of this condition. The affected patients usually present early in childhood with clinical and biochemical evidence of rickets. Physiological replacement dosage of 1,25-dihydroxyvitamin D3 has no therapeutic effect. Responses to pharmacological doses of vitamin D metabolites or long-term calcium infusion have been variable. A case is reported here of an 8 year old girl, of consanguineous parents with vitamin D-dependent rickets, type II, in whom treatment with high dose oral calcium resulted in marked biochemical and radiological improvement. It is concluded that high dose oral calcium treatment is an effective treatment option for patients with vitamin D-dependent rickets type II.

Administration, Oral↗
PubMed1994

Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age.

PURPOSE: To test the efficacy of a protocol for poor-risk neuroblastoma that builds on the following: (1) our favorable previously reported results with dose-intensive use of cyclophosphamide; (2) our retrospective analysis of neuroblastoma chemotherapy reports, which supported the value of high-dose cisplatin and etoposide (VP-16); and (3) the Goldie-Coldman hypothesis that rapid cytoreduction plus the use of non-cross-resistant chemotherapy combinations will decrease the risk of drug resistance. PATIENTS AND METHODS: The N6 protocol included seven courses of high-dose chemotherapy plus surgical resection of bulk disease. Courses 1, 2, 4, and 6 consisted of 6-hour intravenous infusions of cyclophosphamide 70 mg/kg/d on days 1 and 2 (ie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/m2 and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m2 intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m2/d on days 1 to 3 (ie, 600 mg/m2 per course), and 1-hour intravenous infusions of cisplatin 50 mg/m2/d on days 1 to 4 (ie, 200 mg/m2 per course). Courses were to start after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Response was defined by international criteria. RESULTS: Among 24 consecutive previously untreated patients diagnosed with stage 4 neuroblastoma at more than 1 year of age, 21 patients achieved a complete or very good partial remission; one patient had no evidence of disease except by iodine-131-metaiodobenzylguanidine (MIBG) scan, which was markedly improved; and one patient had resolution of extensive metastatic disease, but still had an incompletely resected primary tumor. The sole patient to have a poor response had clinical features at diagnosis that are atypical for neuroblastoma, namely, 8 years of age and an unknown primary tumor. Severe toxicities included myelosuppression, mucositis, and hearing deficits. CONCLUSION: The N6 approach reliably achieves significant cytoreduction against stage 4 neuroblastoma. This may eventuate in an improved cure rate, since consolidative treatments using myeloablative therapy, immunotherapy, or biologic response modifiers such as cis-retinoic acid are most likely to be effective against minimal residual disease.

Abdominal Neoplasms↗
PubMed1994

Preferential amplification of the paternal allele in neuroblastomas with N-myc amplification.

There is increasing evidence that imprinting plays an important role in influencing the parental origin of genes involved in cancer-specific rearrangements. In advanced stage neuroblastomas, both allelic loss of the short arm of chromosome 1 (1p) and amplification of the proto-oncogene N-myc are often seen. Therefore, we analyzed 22 human neuroblastomas with N-myc amplification to determine the parental origin of the N-myc allele that is amplified and the 1p allele that is deleted. We used at least three polymorphisms for both the 1p and the N-myc locus to analyze blood and tumor samples from neuroblastoma patients, as well as blood samples from their parents. We determined that the paternal allele of N-myc was amplified in 12 of 15 informative cases (P = 0.02), and the paternal allele on 1p was lost in 6 of 11 informative cases (P > 0.2). These results suggest that parental imprinting does not appear to affect the 1p allele that is deleted, at least in the cases that we have examined. However, imprinting has an important influence on determining the N-myc allele that is amplified in these tumors, suggesting that the paternal allele is either more highly expressed or more likely to undergo amplification.

Alleles↗
PubMed1993

Disialoganglioside GD2 anti-idiotypic monoclonal antibodies.

Disialoganglioside GD2 is widely expressed among neuroblastomas, melanomas, small-cell lung carcinoma, sarcomas and brain tumors. Immunity directed against this antigen may have anti-tumor utility. Since GD2 is poorly immunogenic, anti-idiotypic antibodies may serve as alternative tumor vaccines. Monoclonal antibody 3F8, a murine IgG3 specific for GD2, has shown excellent tumor-targeting ability in vitro and in vivo. LOU/CN rats were immunized with 3F8 and their spleens were used in somatic-cell hybridization, using SP2/0, P3 and Y3 as fusion partners. Six anti-idiotypic (anti-id) MAbs (C2D8, Idio-2, AIG4, C2H7, C4E4, A2A6) were selected based on their reactivity with 3F8 and non-reactivity with murine IgG3 myelomas. Specificity of each anti-id was demonstrated by using various ELISA: (i) lack of direct binding to solid phase myelomas and serum proteins; (ii) inability of other myelomas to inhibit anti-id binding to 3F8; (iii) absence of cross-reactivity of other myelomas to solid-phase anti-id; (iv) lack of inhibition by anti-id of binding of other ganglioside antibodies to their antigens. Antigen specificity was further examined by inhibition of binding of 3F8 to GD2 on immuno-thin-layer chromatography, and by inhibition of 3F8 immunostaining of neuroblastoma cell lines. These 6 antibodies were demonstrated to be distinct, in view of their cross-reactivity, fusion partners and relative strength of binding to 3F8. Anti-GD2 antibodies were induced after immunization with these anti-id antibodies in C57Bl/6 mice. These rat anti-3F8-idiotypic antibodies with exquisite specificity for anti-GD2 antibodies may be useful in vaccine construction.

Animals↗
PubMed1993

GD2 ganglioside on human T-lymphotropic virus type I-infected T cells: possible activation of beta-1,4-N-acetylgalactosaminyltransferase gene by p40tax.

Ganglioside expression on adult T-cell leukemia (ATL) and human T-cell lymphotropic virus type I (HTLV-I)-infected cells was determined by using a panel of monoclonal antibodies. ATL lines and HTLV-I-infected cells specifically expressed GD2. Leukemia cells from ATL patients generally expressed low levels of GD2 but the percentage of GD2+ cells increased up to 40-70% after in vitro culture in the presence of interleukin 2 for about a week. No other type of leukemia cells and normal peripheral T cells expressed GD2 during in vitro culture under the same conditions. The appearance of GD2 in the cultured ATL cells corresponded with the expression of p40tax, a product of the HTLV-I gene. Peripheral lymphocytes infected with a p40tax-expressing retroviral vector expressed high levels of GD2 in comparison with control lymphocytes containing the neomycin-resistance gene alone. The apparently increased levels of beta-1,4-N-acetylgalactosaminyltransferase (GM2/GD2 synthase) mRNA in these cells were demonstrated by reverse transcription-polymerase chain reaction analysis. Concordance between mRNA expression for the HTLV-I tax1/rex1 genes and the beta-1,4-N-acetylgalactosaminyltransferase gene was also observed in uncultured ATL cells. These results suggest that high GD2 expression was due to neosynthesis from precursor GD3 by increased expression of this enzyme induced by p40tax in vitro and in vivo.

Base Sequence↗
PubMed1993

Development of a method to measure kinetics of radiolabelled monoclonal antibody in human tumour with applications to microdosimetry: positron emission tomography studies of iodine-124 labelled 3F8 monoclonal antibody in glioma.

We present a method to assess quantitatively the immunological characteristics of tumours using radiolabelled monoclonal antibody and positron emission tomography (PET) to improve dosimetry for radioimmunotherapy. This method is illustrated with a glioma patient who was injected with 96.2 MBq of iodine-124 labelled 3F8, a murine antibody (IgG3) specific against the ganglioside GD2. Serial PET scans and plasma samples were taken over 11 days. A three-compartment model was used to estimate the plasma to tumour transfer constant (K1), the tumour to plasma transfer constant k2, the association and dissociation constants (k3, k4) of antibody binding, and the binding potential. Tumour radioactivity peaked at 18 h at 0.0045% ID/g. The kinetic parameters were estimated to be: K1 = 0.048 ml h-1 g-1, k2 = 0.16 h-1, k3 = 0.03 h-1, k4 = 0.015 h-1 and BP = 2.25. Based on these kinetic parameters, the amount of tumour-bound radiolabelled monoclonal antibody was calculated. This method permits estimates of both macrodosimetry and microdosimetry at the cellular level based on in vivo non-invasive measurement.

Brain↗