Biomedical subjects

N K Cheung

Publications and source records attributed to N K Cheung.

At least 55 records · Page 3Linked to original sources

PubMed2000

Induction of Ab3 and Ab3' antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma.

Treatment with anti-G(D2) monoclonal antibody 3F8 (Ab1) at the time of remission may prolong survival for children with stage 4 neuroblastoma. A transient human antimouse antibody (HAMA) response was associated with significantly longer survival (Cheung et al., J. Clin. Oncol., 16: 3053-3060, 1998). Because this response was primarily anti-idiotypic (Ab2), we postulate that the subsequent induction of an idiotype network that included an elevation of anti-anti-idiotypic (Ab3) and anti-G(D2) (Ab3') antibody titers may be responsible for tumor control. Thirty-four patients with stage 4 neuroblastoma diagnosed at >1 year of age were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (31 of 34) or distant bony (29 of 34) metastases at diagnosis. Thirteen patients were treated at second or subsequent remission, and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation; 21 patients were treated in the first remission after N6 chemotherapy. Their serum HAMA, Ab3, and Ab3' titers prior to, at 6, and at 14 months after antibody treatment were measured by ELISA. Among these 34 patients, 14 are alive, and 13 (1.8-7.4 years at diagnosis) are progression free (53-143 months from the initiation of 3F8 treatment) without further systemic therapy. Long-term progression-free survival (PFS) and survival correlated significantly with Ab3' (anti-G(D2)) response at 6 months and with Ab3 response at 6 and 14 months. By defining Ab3 threshold ranging from the ratio of 1.1 to 2.6 above pretreatment level, the difference in PFS and survival between the high-Ab3 and low-Ab3 groups became markedly widened. Similarly, increasing the Ab3' threshold at either 6 or 14 months to 300% above pre-3F8 levels also increased the spread between the high versus low Ab3' groups for both PFS and survival curves. Non-idiotype antibody responses (anti-mouse-IgG3 or anti-tumor nuclear HUD antigen) had no apparent impact on PFS or survival. In conclusion, despite the high-risk nature of stage 4 neuroblastoma, long-term remission without myeloablative therapy can be achieved with 3F8 treatment. Ab3 and Ab3' antibody response correlated with prolonged PFS and survival. We postulate that successful induction of an idiotype network in patients may be responsible for long-term tumor control.

Animals↗

PubMed1999

Treatment of neoplastic meningeal xenografts by intraventricular administration of an antiganglioside monoclonal antibody, 3F8.

Leptomeningeal (LM) neoplastic metastases are painful, debilitating and inevitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic potential. We evaluated 3F8, an anti-G(D2) murine IgG(3) monoclonal antibody (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NMB7) xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in the presence of rat neutrophils or rat complement. Antibody-dependent cellular cytotoxicity (ADCC) was not augmented by recombinant human GM-CSF (rhGM-CSF), rhG-CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysaccharide (LPS). In vivo, continuous intraventricular administration of 3F8 and LPS prevented tumor engraftment, retarded tumor growth and eradicated 3-day-old established xenografts whereas 3F8 alone, LPS alone or F(ab)'(2) plus LPS had no or only marginal effects. Tumor establishment in brain was completely prevented in 36% of animals implanted with SKMEL-1 and 65% of animals implanted with NMB7. Twenty percent of established xenografts around the brain were eradicated but all animals had persistent tumor in the lumbosacral meninges despite treatment. Continuous intraventricular infusion of LPS produced a variable polymorphonuclear (PMN) pleocytosis that was dose-dependent. Continuous intraventricular infusion of 3F8 produced immunohistochemically detectable attachment to 86% of persistent brain deposits of tumor but <1% of spinal lumbosacral deposits. We conclude that regional therapy with anti-G(D2) MAb could target neutrophils to inhibit LM tumor growth. However, optimal activation and mobilization of neutrophils into the cerebrospinal fluid (CSF) and improved penetration of MAb to tumor sites remain critical variables.

Animals↗

PubMed1999

Detection of neuroblastoma in bone marrow by immunocytology: is a single marrow aspirate adequate?

BACKGROUND: Except at diagnosis and relapse, when gross disease is present, histologic evaluation is less sensitive than immunocytology (IC) of bone marrow for detecting metastatic neuroblastoma. We examined whether the chance of a positive IC from a single marrow site was comparable to an IC of pooled marrow from multiple sites. PROCEDURE: We carried out 47 marrow examinations on 29 patients with high-risk neuroblastoma on therapy. Each examination consisted of histologic evaluation of four aspirates and two biopsies (six sites), IC of a 2.5-5-mL heparinized sample from a single site (the right posterior iliac crest; IC-RPIC), as well as IC of 8-10 mL of heparinized marrow pooled from bilateral anterior and bilateral posterior iliac crests (IC-pooled). IC was performed using a panel of monoclonal antibodies specific for ganglioside GD2. RESULTS: The number of GD2-positive tumor cells detected by IC-pooled had a strong linear correlation with that by IC-RPIC (R = 0.91), although IC-pooled detected an average of 3.3 times more GD2-positive cells. Of 47 examinations, 15 tested positive by histology (6 sites), 20 by IC- pooled, and 17 by IC-RPIC. Among 29 patients, the level of agreement between IC-RPIC and IC-pooled was generally good (kappa statistic > or = 0.72), giving a false negative rate of < or = 30%. CONCLUSIONS: Compared to conventional histologic examinations, immunocytology of a single marrow aspirate generally agrees with that of marrow pooled from six sites. However, the false negative rate may be too high in the setting of examination prior to bone marrow or stem cell harvest.

Antibodies, Monoclonal↗

PubMed1999

Synovial sarcoma mimicking desmoplastic small round-cell tumor: critical role for molecular diagnosis.

BACKGROUND: The identification of recently described nonrandom chromosomal defects specific for various small round-cell and spindle-cell sarcomas can eliminate diagnostic uncertainty arising from the clinical and histopathologic overlap of soft tissue neoplasms. METHODS: A 26-year-old man presented with bulky abdominal-pelvic disease. Immunohistochemical and molecular studies on tumor were performed. Treatment was instituted using cycles of high-dose cyclophosphamide (4,200 mg/m2) with doxorubicin (75 mg/m2). RESULTS: Clinical findings pointed to desmoplastic small round-cell tumor. The tumor was histologically undifferentiated and immunoreactive for vimentin but negative for other markers. Reverse transcriptase-polymerase chain reaction revealed the SYT/SSX2 fusion transcript of the synovial sarcoma t(X;18) chromosomal rearrangement. The high-dose chemotherapy, plus surgery, achieved a complete remission, but recurrent disease emerged 13 months from diagnosis. CONCLUSIONS: This clinically unique case of synovial sarcoma highlights how the use of now readily available molecular techniques will allow more accurate appraisals of the incidence and anatomic distribution of soft tissue neoplasms-information that bears upon pathogenesis and treatment. This case confirms the utility of high-dose alkylator-based therapy for synovial sarcoma. It also demonstrates that with nonlocalized solid tumors, the eradication of minimal residual disease remains an elusive goal. One alternative involves immunologic attack against markers derived from tumor-specific chromosomal defects such as those found in our patient.

Abdominal Neoplasms↗

PubMed1999

Clinically critical impact of molecular genetic studies in pediatric solid tumors.

BACKGROUND: Standard cytogenetic techniques are time-consuming and often not informative with solid tumors. In contrast, the reverse transcriptase-polymerase chain reaction (RT-PCR) is a readily available technique that can rapidly detect tumor-specific chromosomal rearrangements, even in small biopsy specimens. We present cases depicting the importance of including molecular diagnostic studies in the routine evaluation of pediatric solid tumors. PROCEDURE: We used RT-PCR to detect chimeric transcripts specific for major pediatric solid tumors, including peripheral primitive neuroectodermal tumor (pPNET), alveolar rhabdomyosarcoma (ARMS), and desmoplastic small round-cell tumor (DSRCT). We reviewed six recent cases in which the initial diagnosis was changed by the results of RT-PCR. RESULTS: Highly unusual or nonspecific clinical and/or histopathologic findings led to the initial diagnoses of neuroblastoma in three patients and DSRCT, leukemia, and carcinoma in one patient each. The final diagnoses after RT-PCR studies were pPNET in three patients, ARMS in two patients, and DSRCT in one patient. RT-PCR results led to early corrections in the diagnosis in two patients, but four patients received treatment not considered optimal for the neoplasms ultimately diagnosed, including three who, despite presenting with localized tumors that have a >70% cure rate with standard therapy, have died or are dying of disease. CONCLUSIONS: Molecular genetic studies on solid tumors can clarify the diagnosis in seemingly straightforward as well as in overtly problematic cases. These diagnostic distinctions are now critical as disease-specific and risk-directed therapies have emerged.

Adolescent↗

PubMed1999

99mTc-monoclonal antibody radiolabeled via hydrazino nicotinamide derivative for imaging disialoganglioside G(D2)-positive tumors.

3F8 is a murine IgG3 monoclonal antibody (MAb) selective for the ganglioside G(D2). Previous studies using 131I-3F8 have shown great potential in the imaging of neuroectodermal tumors and the therapy of human neuroblastoma. 131I is commonly used in radioimmunodiagnosis, but its relatively long half-life (8 days) and its high energy gamma-emission (364 KeV) are suboptimal for imaging purposes when compared with 99mTc (6 h and 140 KeV, respectively). To label 3F8 with 99mTc, the antibody was first coupled with a heterobifunctional linker, succinimidyl-6-hydrazinonicotinate hydrochloride (SHNH), obtaining a hydrazinonicotinamide-antibody conjugate. Using 99mTc-Tricine as the precursor complex, 3F8-SHNH was coupled efficiently to 99mTc, resulting in >90% radiometal incorporation, with a specific activity >10 mCi/mg and retaining full immunoreactivity. Immunoscintigraphy at 6, 22, and 46 h after intravenous injection of 1 mCi of 99mTc-3F8 showed selective neuroblastoma localization in xenografted nude mice, comparable to that obtained with the injection of 100 microCi of 131I-3F8. Biodistribution studies of 131I-3F8 and 99mTc-3F8 in mice demonstrated comparable %ID/g uptake in tumor (with a T/B ratio: approximately 2.5 at 24 h and approximately 3.5 at 48 h) and normal organs, including blood, except for spleen and liver which had about a three times higher uptake of the 99mTc conjugate. In conclusion, 99mTc can be coupled conveniently at high specific activity to 3F8 without compromising immunoreactivity. SHNH appears to be a useful linker for 99mTc in tumor diagnostic imaging and may have potential utility in coupling other radioisotopes (e.g., 94mTc) for positron imaging and therapy.

Animals↗

PubMed1999

Intrathecal administration of an anti-ganglioside antibody results in specific accumulation within meningeal neoplastic xenografts in nude rats.

Intrathecal (i.t.) administration of monoclonal antibodies (MAbs) represents a new therapeutic approach for the treatment of leptomeningeal (LM) cancer, which is presently rapidly fatal. In this study, we quantitated the accumulation of an intrathecally administered anti-ganglioside GD2 MAb (3F8) within leptomeningeal neoplastic xenografts of GD2 positive melanoma and neuroblastoma in nude rats by measuring concentrations of radiolabeled and unmodified MAbs and by immunohistochemistry. Intrathecal administration of 125I-3F8 resulted in area under the tissue concentration versus time curve (AUC) values in SK-MEL-1 melanoma xenografts (53.1 microCi*h/g) that were 14-fold greater than in corresponding blood (3.9 microCi*h/g), whereas i.t. administration of a control nonspecific MAb resulted in AUC values in tumors (7.1 microCi*h/g) that were less than those in blood (9.5 microCi*h/g). Administration of acetazolamide and furosemide, which slow the clearance of IgG MAb from rat cerebrospinal fluid resulted in a fivefold increase in AUC of 125I-3F8 in melanoma (262.9 microCi*h/g). The highest concentration of 125I-MAb in tumor after i.t. administration was seen at the first sampling time of 2 h, and this fell to 50% of maximum values at 8-16 h. Pharmacokinetic analysis of unmodified MAb demonstrated retention of MAb within the LM space of animals with tumor. The concentration of MAb 3F8 appearing in serum after i.t. administration was 10-fold lower in animals with melanoma xenografts than in those without tumor implants. Radiation dose estimates after intraventricular administration of radiolabeled MAb indicated delivery to tumor of 1,870 rad/mCi of 125I-3F8 but only 40 rad/mCi of 125I-labeled control MAb. These results indicate that anti-ganglioside MAbs and other MAbs directed to tumor-associated antigens are excellent candidates for i.t. treatment of appropriate leptomeningeal cancers in humans.

Acetazolamide↗

PubMed1999

Oral etoposide for refractory and relapsed neuroblastoma.

PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m(2) taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m(2) to 3,935 mg/m(2) (median, 2,300 mg/m(2)). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.

Administration, Oral↗

PubMed1999

Association between molecular detection of GAGE and survival in patients with malignant melanoma: a retrospective cohort study.

We used GAGE as a molecular marker to identify melanoma cells with metastatic potential in the peripheral blood and the bone marrow. One hundred thirty-three patients with malignant melanoma (21 clinical stage II, 74 stage III, and 38 stage IV) had a single marrow and/or blood sample drawn immediately prior to surgical resection. Simultaneous bone marrow and blood samples (85 patients), marrow-only samples (35 patients), and blood-only samples (13 patients) were examined for the presence of GAGE expression using reverse transcription-PCR. GAGE expression was associated with adverse overall patient survival, measured from the time of sampling (P = 0.01). When data were stratified for clinical stage, median survival was statistically longer among GAGE-negative patients in the stage III cohort only (P = 0.01). In a multivariate model, only GAGE positivity in blood and/or marrow and clinical stage were significant prognostic variables. It was the detection of GAGE in blood but not marrow that was associated with poor survival. The detection of blood GAGE by reverse transcription-PCR has significant adverse implications for overall survival of patients with malignant melanoma in this cohort, and it warrants further investigation.

Adult↗

PubMed1998

Association of CYP3A4 genotype with treatment-related leukemia.

Epipodophyllotoxins are associated with leukemias characterized by translocations of the MLL gene at chromosome band 11q23 and other translocations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyllotoxin catechol and quinone metabolites, which could damage DNA. There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4-V) that might alter the metabolism of anticancer drugs. We examined 99 de novo and 30 treatment-related leukemias with a conformation-sensitive gel electrophoresis assay for the presence of the CYP3A4-V. In all treatment-related cases, there was prior exposure to one or more anticancer drugs metabolized by CYP3A. Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.026; Fisher's Exact Test, FET). Nine of 42 de novo leukemias with MLL gene translocations (21%), and 0 of 22 treatment-related leukemias with MLL gene translocations carried the CYP3A4-V (P = 0. 016, FET). This relationship remained significant when 19 treatment-related leukemias with MLL gene translocations that followed epipodophyllotoxin exposure were compared with the same 42 de novo cases (P = 0.026, FET). These data suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabolism by CYP3A4 may contribute to the secondary cancer risk. The CYP3A4-W genotype may increase production of potentially DNA-damaging reactive intermediates. The variant may decrease production of the epipodophyllotoxin catechol metabolite, which is the precursor of the potentially DNA-damaging quinone.

Adolescent↗

PubMed1998

Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes.

Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neuroblastoma, small-cell lung carcinoma, melanoma, and other human tumors. Recognition of GD2 was provided by a single-chain antibody derived from the GD2-specific monoclonal antibody 3G6. We demonstrate that the chimeric receptor 3G6-CD28 provides CD28 signaling upon specific recognition of the GD2 antigen on tumor cells. Human primary T lymphocytes retrovirally transduced with 3G6-CD28 secrete interleukin 2, survive proapoptotic culture conditions, and selectively undergo clonal expansion in the presence of an antiidiotypic antibody specific for 3G6-CD28. Polyclonal CD8(+) lymphocytes expressing 3G6-CD28 are selectively expanded when cultured with cells expressing allogeneic major histocompatibility complex class I together with GD2. Primary T cells given such an antigen-dependent survival advantage should be very useful to augment immune responses against tumor cells.

Animals↗

PubMed1998

Antibodies against GD2 ganglioside can eradicate syngeneic cancer micrometastases.

After 10 years of clinical trials in patients with advanced cancer, monoclonal antibodies (mAbs) against cell surface antigens have not lived up to their initial promise. One such cell surface antigen is the ganglioside GD2. GD2 is richly expressed at the cell surfaces of human neuroblastomas, sarcomas, and melanomas. We have described a murine lymphoma (EL4) that is syngeneic in C57BL/6 mice and expresses GD2, a mAb against GD2 (mAb 3F8), and we have prepared a conjugate vaccine (GD2-keyhole limpet hemocyanin plus immunological adjuvant QS-21) that consistently induces antibodies against GD2. We demonstrate here, for the first time in a syngeneic murine model, that passively administered and vaccine-induced antiganglioside antibodies prevent outgrowth of micrometastases, and we use this model to establish some of the parameters of this protection. The level of protection was proportional to antibody titer. Treatment regimens resulting in the highest titer antibodies induced the most protection, and protection was demonstrated even when immunization was initiated after tumor challenge. Treatment with 3F8 1, 2, or 4 days after i.v. tumor challenge was highly protective, but waiting until 7 or 10 days after challenge resulted in minimal protection. The results were similar whether number of liver metastases or survival was used as the end point. These results suggest that unmodified mAbs or antibody-inducing vaccines against GD2 (and possibly other cancer cell surface antigens) should be used exclusively in the adjuvant setting, where circulating tumor cells and micrometastases are the primary targets.

Adjuvants, Immunologic↗

PubMed1998

Neuroblastoma and treatment-related myelodysplasia/leukemia: the Memorial Sloan-Kettering experience and a literature review.

PURPOSE: To assess treatment-related myelodysplasia/leukemia (t-AML) in neuroblastoma patients by a review of the Memorial Sloan-Kettering Cancer Center (MSKCC) data and the literature. PATIENTS AND METHODS: We studied 380 previously untreated and treated MSKCC patients. Low-risk patients received no cytotoxic therapy. High-risk patients received the N4, N5, or N6 regimens. Dosing per cycle and cumulative dosing of leukemogenic agents peaked with N6, which included four cycles of cyclophosphamide 4,200 mg/m2 and doxorubicin 75 mg/m2, plus three cycles of cisplatin 200 mg/m2 and etoposide 600 mg/m2. We reviewed the literature. RESULTS: t-AML occurred in six MSKCC patients, which included three of 53 patients in whom the only chemotherapy consisted of N6, and three patients treated for relapsed or refractory neuroblastoma; no case of leukemia emerged among the 50 low-risk patients. Four cases were found incidentally in routine follow-up bone marrow tests. The 36-month cumulative incidence of t-AML in the N6 cohort was 7% (95% confidence interval, 0 to 15). Published data parallel the MSKCC experience in that t-AML after neuroblastoma was once rare but has become less so since the mid-1980s, when the intensified use of topoisomerase-II inhibitors and alkylators first gained wide acceptance and produced better response rates and longer survival. CONCLUSION: Neuroblastoma itself is not associated with a host susceptibility to leukemia. However, current neuroblastoma treatment programs that use high-dose cyclophosphamide, cisplatin, and topoisomerase-II inhibitors may entail a considerable risk for t-AML. The incidence of t-AML in neuroblastoma patients may be underestimated because treatment and clinical factors can mask its presence. Efforts to devise effective but less leukemogenic treatment for neuroblastoma or to truncate leukemogenic therapy, eg, by exploiting molecular techniques for the early identification of complete remission, are warranted.

Antineoplastic Agents↗

PubMed1998

High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors.

PURPOSE: To help fill the gap in knowledge about the risk of leukemia from repetitive high-dose use of alkylating agents and topoisomerase-II inhibitors in young patients with solid tumors. METHODS: Poor-risk solid tumors were treated with four courses of cyclophosphamide (4,200 mg/m2)/ doxorubicin (75 mg/m2), and three courses of ifosfamide (9,000 mg/m2)/etoposide (500 mg/m2). The cumulative incidence of treatment-related myelodysplasia/ leukemia (t-AML) was calculated using the method of competing risks. The expected number of leukemic events was calculated by applying national incidence rates to person-years classified by age and sex. RESULTS: Among 86 patients (median age, 17 years) monitored for 6 to 88 months (median, 24), five cases of t-AML were detected at 10 to 37 months (median, 17). The expected number of leukemic events in this cohort was .001. Clinical and cytogenetic findings implicated prior alkylator therapy in three cases and prior treatment with topoisomerase-II inhibitors in two. At 40 months, the cumulative incidence of t-AML was 8% (SE 7%). CONCLUSION: Repetitive high-dose use of alkylating agents given with topoisomerase-II inhibitors is strongly leukemogenic, even with modest cumulative doses of each drug. This finding is notable for the following reasons: (1) it undermines predictions that limited use of high-dose chemotherapy might be minimally leukemogenic, and (2) it contrasts strikingly with the previously reported low risk of t-AML following treatment of pediatric solid tumors with chemotherapy lacking the alkylator dose-intensity and prominence of etoposide that are hallmarks of current regimens.

Adolescent↗

PubMed1998

Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age.

PURPOSE: To eradicate minimal residual disease with anti-G(D2) monoclonal antibody 3F8 in stage 4 neuroblastoma (NB) diagnosed at more than 1 year of age. PATIENTS AND METHODS: Thirty-four patients were treated with 3F8 at the end of chemotherapy. Most had either bone marrow (n=31) or distant bony metastases (n=29). Thirteen patients were treated at second or subsequent remission (group I) and 12 patients in this group had a history of progressive/persistent disease after bone marrow transplantation (BMT); 21 patients were treated in first remission following N6 chemotherapy (group II). RESULTS: Before 3F8 treatment, 23 patients were in complete remission CR, eight in very good partial remission (VGPR), one in partial remission (PR), and two had microscopic foci in marrow. Twenty-five had evidence of NB by at least one measurement of occult/minimal tumor (iodine 131[(131)I]-3F8 imaging, marrow immunocytology, or marrow reverse-transcriptase polymerase chain reaction [RT-PCR]). Acute self-limited toxicities of 3F8 treatment were severe pain, fever, urticaria, and reversible decreases in blood counts and serum complement levels. There was evidence of response by immunocytology (six of nine), by GAGE RT-PCR (seven of 12), and by (131)I-3F8 scans (six of six). Fourteen patients are alive and 13 (age 1.8 to 7.4 years at diagnosis) are progression-free (40 to 130 months from the initiation of 3F8 treatment) without further systemic therapy, none with late neurologic complications. A transient anti-mouse response or the completion of four 3F8 cycles was associated with significantly better survival. CONCLUSION: Despite high-risk nature of stage 4 NB, long-term remission without autologous (A)BMT can be achieved with 3F8 treatment. Its side effects were short-lived and manageable. The potential benefits of 3F8 in consolidating remission warrant further investigations.

Antibodies, Monoclonal↗

PubMed1998

3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: a phase II study.

3F8 is an IgG3 murine monoclonal antibody directed against the ganglioside GD2. In a phase II study, 3F8 was administered i.v. to 16 patients (pts) who had stage 4 neuroblastoma. Response was seen in bony lesions (2 of 7 pts) and marrow (3 of 8 pts). Acute toxicities of pain, fever, urticaria, hypertension, hypotension and anaphylactoid reactions were self-limited and manageable. Three pts are long-term survivors between 79-130+ months after 3F8 treatment without additional systemic therapy and no delayed neurological complications. The potential benefits of 3F8 when added to chemoradio-therapy warrant further investigation.

Abdominal Pain↗

PubMed1998

Pharmacokinetics of IgG and IgM anti-ganglioside antibodies in rats and monkeys after intrathecal administration.

Intrathecal (i.t.) administration of monoclonal antibodies (mAbs) represents a new therapeutic approach for the treatment of leptomeningeal cancer, which is rapidly fatal. This study describes the pharmacokinetics of intrathecally administered mAbs in rats and monkeys to optimize their use for regional antineoplastic therapy. We hypothesized that mAbs, which are high-molecular-weight, polar compounds, would be eliminated from the cerebrospinal fluid (CSF) at the same rate as bulk flow of CSF. We found that an IgM mAb was cleared from rat CSF at the rate of CSF bulk flow (0.0041 ml/min), but an IgG mAb was cleared at a faster rate (0.011 ml/min). We attempted to reduce the CSF clearance of an IgG mAb by administration of acetazolamide and furosemide, which inhibit the rate of CSF production and CSF bulk flow. We demonstrated that the administration of acetazolamide and furosemide reduced the clearance of IgG mAb from rat CSF by 58%. These results establish that bulk flow of CSF determines a minimum rate of elimination from the CSF for IgM mAbs and that additional mechanisms operate to clear IgG mAbs from the CSF. Inhibition of CSF production by acetazolamide and furosemide increased the area under the CSF concentration vs. time curve of IgG mAbs in the CSF. The increased area under the CSF concentration vs. time curve is likely to improve the therapeutic index of these agents for i.t. therapy.

Animals↗

PubMed1998

Disialoganglioside G(D2) loss following monoclonal antibody therapy is rare in neuroblastoma.

Ganglioside GD2 is abundant on human neuroblastoma (NB). Monoclonal antibody 3F8 targeted to GD2 may have imaging and therapeutic potential. Antigen-negative clones can escape immune-mediated attack, leading to clinical resistance or recurrence. Among 95 evaluable patients treated i.v. with 3F8 (94 stage 4 and 1 stage 3), 66 received nonradiolabeled 3F8, 11 received 131I-labeled 3F8 (8-28 mCi/kg) with autologous bone marrow rescue, and 18 received both forms of treatment. Prior to treatment, 91 patients tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 68), tumor immunohistochemistry (n = 20), or diagnostic radioimmunoscintigraphy only (n = 3). Of 62 patients who had refractory or recurrent NB following 3F8 treatment, 61 (98%) tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 51) or tumor immunohistochemistry (n = 10). The sole tumor that lost GD2 expression underwent phenotypic transformation into a pheochromocytoma-like tumor. The persistence of GD2 expression in refractory or recurrent NB suggests that complete antigen loss is an uncommon event and cannot account for treatment failure.

Antibodies, Monoclonal↗