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Journal of Clinical Oncology, Vol 19, Issue 22 (November), 2001: 4189-4194
© 2001 American Society for Clinical Oncology

Phase II Trial of the Anti-GD2 Monoclonal Antibody 3F8 and Granulocyte-Macrophage Colony-Stimulating Factor for Neuroblastoma

By Brian H. Kushner, Kim Kramer, Nai-Kong V. Cheung

From the Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Brian H. Kushner, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: kushnerb{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To describe oncolytic effects of treatment with anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with neuroblastoma (NB).

PATIENTS AND METHODS: Patients were eligible for 3F8/GM-CSF if intensive therapy had not eradicated potentially lethal NB. One cycle consisted of GM-CSF (subcutaneous bolus) on days 1 through 5, 11, and 12, and GM-CSF (2-hour intravenous [IV] infusion) followed after a 1-hour interval by 3F8 (1.5-hour IV infusion) on days 6 through 10 and 13 through 17. GM-CSF was dosed at 250 µg/m2/d on days 1 through 7 and at 500 µg/m2/d on days 8 through 17. 3F8 was dosed at 10 mg/m2/d (100 mg/m2/cycle). 3F8 was given with an opiate and an antihistamine. Patients without progressive disease (PD) or elevated human antimouse antibody titers could be treated again beginning 3 weeks after completion of a cycle.

RESULTS: Among 19 patients treated for NB resistant to induction therapy, 12 of 15 had complete remission (CR) of bone marrow (BM) disease, and three others who had less than partial responses achieved prolonged progression-free survival (one remains on study at 21+ months, two had PD at 12 and 17 months). Among patients treated for recurrent NB resistant to retrieval therapy, five of 10 had CR in BM. The 15 patients treated for PD fared poorly, although two had scintigraphic findings suggestive of a short-term response. Side effects were limited to readily manageable pain and, less commonly, rash of short duration; hence, patients were treated as outpatients.

CONCLUSION: 3F8/GM-CSF is well tolerated and shows promise for treatment of minimal residual NB in BM.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
INTENSIVE CHEMOTHERAPY achieves major regressions of stage 4 neuroblastoma (NB) diagnosed in children older than 1 year, but lethal relapse remains the rule, hence the need for novel therapeutic approaches. Mobilizing host immune defenses to attack NB is one means for bypassing chemoresistance. 3F8 is a murine immunoglobulin (Ig)G3 monoclonal antibody that is well suited for targeted immunotherapy. 3F8 reacts with ganglioside GD2,1 which is expressed at high density on NB (but has limited distribution in normal human tissues2), is not modulated from the cell surface when bound by antibodies, and is rarely lost.3 Scintigraphy with radiolabeled 3F8 confirms that 3F8 localizes selectively to GD2-positive tumor in patients.4 In vitro, 3F8 mediates destruction of human tumor cells by human complement and by human mononuclear and granulocytic cells.5-8 3F8 activates complement on malignant neuroblasts9; the release of complement fragments in patients may elicit an inflammatory influx of leukocytes capable of lysing 3F8-labeled tumor cells.

3F8 phase I/II studies have shown promising anti-NB effects and manageable toxicity.10-12 Granulocyte-macrophage colony-stimulating factor (GM-CSF) can potentially amplify 3F8 antitumor activity by increasing granulocyte numbers13,14 and by priming those effector cells for greater cytotoxicity.8,15 We now report results of a phase II study using these two agents together.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients were eligible for this phase II trial of 3F8 (prepared as described4) and yeast-derived human recombinant GM-CSF (Sargramostim, Immunex Corporation, Seattle, WA) if they had potentially lethal NB and were not in complete or very good partial remission. Informed consent for treatment was obtained in accordance with hospital guidelines.

Disease status was assessed every 2 to 3 months with computed tomography, technetium-99m bone scan, iodine-131 or iodine-123 meta-iodobenzylguanidine scan, urine catecholamine measurements, and bone marrow (BM) studies (aspirates from bilateral anterior and bilateral posterior iliac crests and biopsies from two to four different sites). BM studies were repeated more frequently.

Disease status was defined by international criteria16: complete response (CR), no evidence of disease; very good partial response, primary mass reduced by 90% to 99%, no evidence of distant disease except for skeletal residua, and catecholamines normal; partial response, more than 50% decrease in measurable disease and <= one positive BM site; mixed response, more than 50% decrease of any lesion with less than 50% decrease in any other; no response, less than 50% decrease but less than 25% increase in any existing lesion; and progressive disease (PD), new lesion or more than 25% increase in an existing lesion.

One treatment cycle consisted of subcutaneous boluses of GM-CSF on days 1 through 5 (Wednesday through Sunday) and on days 11 and 12 (Saturday and Sunday), and 2-hour intravenous (IV) infusions of GM-CSF followed by (after a 1-hour interval) 1.5-hour IV infusions of 3F8 on days 6 through 10 (Monday through Friday) and on days 13 through 17 (Monday through Friday). GM-CSF was dosed at 250 µg/m2/d on days 1 through 7 and at 500 µg/m2/d beginning on day 8 (the third day of combined 3F8/GM-CSF). GM-CSF was withheld when the absolute neutrophil count was more than 20,000/µL. 3F8 dosage was fixed at 10 mg/m2/d (100 mg/m2 per cycle). Because of expected pain and hives,10-12 3F8 was given with an antihistamine and an opiate.

3F8/GM-CSF could be repeated beginning a minimum of 3 weeks after completion of a cycle. Patients came off study if they developed PD or if they formed elevated human antimouse antibody (HAMA) titers (measured as described17) after four cycles (40 days of 3F8); otherwise, patients could be re-treated through 24 months from study entry.

Beginning in November 2000, treatment with cis-retinoic acid (160 mg/m2 x 14 days,18 then a minimum of 14 days before repeat) was started in patients who achieved a CR to 3F8/GM-CSF. Cis-retinoic acid could not be taken on the same days as 3F8 administration.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Of 45 patients (53% were male), 43 had stage 4 and two had multiply-recurrent soft-tissue NB. All 45 were older than 1 year at diagnosis; they were 2 to 22 (median 6) years old at study entry. All patients had previously received a stem-cell transplant and/or high-dose chemotherapy, ie, cyclophosphamide >= 4,000 mg/m2, ifosfamide >= 10 g/m2, cisplatin 200 mg/m2, or carboplatin 1,000 mg/m2 per cycle. 3F8/GM-CSF was started 1 to 9 months (median, 2 months) after prior chemotherapy.

Effects Against Primary Refractory Disease
The 19 patients treated for NB that had responded incompletely to induction (primary refractory disease) started 3F8/GM-CSF 6 to 26 months (median, 11 months) from diagnosis (Table 1). Evidence of anti-NB effect included the following: CR in BM (confirmed by repeated examinations) in 12 (80%) of 15 patients with refractory BM disease; long progression-free survival—21+, 12, and 17 months—in three patients (nos. 1, 4, and 15, respectively) who had less than partial responses; and normalization of catecholamine levels in one patient (no. 10) who had no other evidence of NB. In addition, catecholamine levels normalized and prolonged (15+ months) CR in BM was documented after 3F8/GM-CSF in one patient (no. 8) who was not assessable for response because (1) cis-retinoic acid was taken before and soon after 3F8/GM-CSF, and (2) although NB had been detected in BM intermittently since diagnosis, BM tests just before 3F8/GM-CSF showed no extrinsic cells.


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  		Table 1.  Patients Treated for Primary Refractory Disease (n = 19)
 
Overall, in this group, eight patients are progression-free: one patient (no. 3) is a long-term event-free survivor (75+ months), one patient (no. 12) came off study after two cycles because of suspected secondary myelodysplasia but remains well (with normal cytogenetics) at 15+ months on cis-retinoic acid and no other treatment, and six patients are progression-free and remain on study at 3+, 5+, 10+, 15+, 19+, and 21+ months (four take cis-retinoic acid, with timing noted in Table 1). Of the other 11 patients treated with 3F8/GM-CSF for primary refractory NB, eight had PD at 1, 4, 5, 6, 9, 12, 15, and 17 months, and three came off study after one cycle because they formed HAMA and still had evidence of NB (patients no. 6 and 9) or because cytogenetic abnormalities showing secondary leukemia were present in BM cells obtained immediately before study entry (patient no. 16).

Effects Against Relapsed or PD
The 11 patients treated for recurrent NB that was refractory to retrieval therapy (secondary refractory disease) started 3F8/GM-CSF 3 to 14 months (median, 6.5 months) after relapse (Table 2). One patient (no. 20) was treated for multiply-recurrent NB in soft tissue and had PD. The other 10 patients had refractory BM disease: CR in BM was confirmed in repeated examinations in three patients (nos. 22, 26, and 27), and a transient CR in BM was noted in two patients (nos. 24 and 25). Overall, nine patients came off study after one or two cycles because of PD (n = 7), secondary myelodysplasia (n = 1), or high HAMA titers while disease remained present (n = 1); one patient (no. 27) completed the four planned cycles of 3F8/GM-CSF in CR, but had PD 4 months off therapy (11 months from study entry); and one patient (no. 30) is progression-free at 6+ months and continues on study.


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  		Table 2.  Patients Treated for Secondary Refractory Disease (n = 11)
 
The 15 patients treated for PD received only one (n = 12) or two (n = 3) cycles of 3F8/GM-CSF because of continued PD. At study entry, all 15 had bulky disease, visibly enlarging masses, and/or tumor-related bone pain. Two had iodine-131 meta-iodobenzylguanidine scan or OctreoScan findings suggestive of a short-term response.

Toxicity
3F8/GM-CSF was well tolerated, so treatment was routinely outpatient. No patient experienced major side effects of GM-CSF, such as effusions or pulmonary edema. Fevers occasionally occurred during the 17-day treatment period (fevers have also been associated with 3F8 treatment minus GM-CSF). One patient developed a dry, hacking cough that persisted for several hours.

Treatment with 3F8 was marked by pain and, less often, clinically insignificant urticarial rashes. Pain typically began in the final 30 minutes of the 3F8 infusion, lasted up to 30 minutes, and affected abdomen and back. One patient (no. 19) repeatedly became hypotensive during 3F8 infusions; the problem resolved with brisk IV hydration. No liver, renal, or cardiac toxicity occurred. One patient (no. 16) developed marked gastric distension during the first week post-3F8, compatible with atonia. Possible contributing factors included prior treatment with neurotoxic chemotherapy and extensive paraspinal surgery. No other patient had evidence of neurotoxicity.

Neutrophilia and eosinophilia occurred in the second week of 3F8/GM-CSF cycles; monocytosis was not seen. There were no clinically significant changes in platelet counts.

Patients treated with 3F8/GM-CSF less than 2 to 3 months after strongly immunosuppressive therapy did not develop prolonged elevations in HAMA titers, but other patients developed high HAMA titers that precluded further treatment with 3F8.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Combined use of 3F8 and GM-CSF entailed readily manageable side effects—principally pain and hives—and produced anti-NB effects in BM. 3F8/GM-CSF was ineffective against PD and soft-tissue masses. GM-CSF at 250 to 500 µg/m2 did not cause the major toxicities associated with this cytokine in adults, such as fluid retention, pulmonary edema, pleural and pericardial effusions, and venous thrombosis.19 The treatment was amenable to the outpatient setting and was not limited by lingering noxious sequelae from prior intensive cytotoxic therapies.

Several considerations prompted us to use GM-CSF with the aim of augmenting 3F8 anti-NB activity. First, GM-CSF increases neutrophil and eosinophil production and enhances antibody-dependent cellular cytotoxicity against NB.8,15 Second, GM-CSF is well tolerated in children at bioactive dosing in the range of 300 to 640 µg/m2/d (hence, our choice of 250 to 500 µg/m2 for daily dosing).13,14 Third, GM-CSF has no known trophic effects on solid tumors.20,21 Finally, eosinophilic infiltration of some cancers has favorable prognostic significance, and eosinophils exhibit potent antitumor activity in animal models.22,23

Enhancing granulocytic antitumor potency is particularly warranted in patients with poor-risk NB for at least two reasons: (1) the strongly immunosuppressive standard therapy for this population results in prolonged severe lymphopenia, but granulocyte production is only transiently suppressed and granulocytes from patients retain excellent cytotoxic capacities15; and (2) neuroblasts are deficient in the expression of surface antigens required for antibody-dependent cytotoxicity by lymphocytes, ie, major histocompatibility complex and intercellular adhesion molecule-1.24,25

We chose to administer GM-CSF by a 2-hour IV infusion because GM-CSF disappears rapidly (< 2 to 3 hours) from the blood with that schedule.14,26,27 We wished to avoid the prolonged (> 12 hours) bioactive levels in blood associated with the subcutaneous route; our concern was that elevated serum levels of GM-CSF might impede granulocyte trafficking into tissues. This possibility was raised by a study in which patients who received 24-hour IV infusions of GM-CSF after autologous BM transplantation had decreased migration of granulocytes to a sterile inflammatory site (skin window).28 The findings were viewed as consistent with the neutrophil migration inhibitory and concentration-dependent chemotaxis properties of GM-CSF.

After the first cycle of 3F8/GM-CSF, patients who had not previously been irradiated received local radiotherapy (21 Gy, as described29) to the primary site. This policy was adopted after two patients (patients no. 13 and 26) relapsed in the primary site despite continuing responses in BM. Recently, based on evidence that treatment with cis-retinoic acid can prolong CR,18 we have also adopted a policy to use this agent between cycles of 3F8/GM-CSF in patients who achieve CR.

Two other anti-GD2 monoclonal antibodies—the murine 14G2a and the chimeric human-murine ch14.18—have undergone clinical testing in NB patients.30-36 Each produced encouraging anti-NB results with tolerable toxicity when administered alone30-32,35 or with GM-CSF or interleukin-2.33,34,36 GM-CSF was dosed at 250 to 300 µg/m2/d from 3 to 8 days before antibody administration, through 3 to 6 days after the last dose of antibody, and was given subcutaneously except in one study,36 in which it could also be administered (as in our study) by a 2-hour IV infusion followed (after a 1-hour interval) by IV infusion of the antibody. The conclusions were that treatment with anti-GD2 monoclonal antibodies may prove most beneficial against minimal residual NB, and that their use with GM-CSF was warranted.

Our experience with 3F8 also suggests that a low tumor burden is the optimal context for immunotherapy with anti-GD2 antibodies. We therefore now use 3F8/GM-CSF to consolidate CR posttransplantation (results to be reported after longer follow-up), as well as to treat refractory NB, but we no longer use it for PD or for bulky soft-tissue disease.

HAMA formation can limit the clinical utility of mouse antibodies such as 3F8; indeed, several of our patients were taken off study because they developed high HAMA titers (which precluded early re-treatment) and still had evidence of NB. However, persistently elevated HAMA titers did not emerge in patients treated with 3F8/GM-CSF within 2 to 3 months of strongly immunosuppressive therapy.

We have previously presented evidence consistent with the hypothesis that 3F8 achieves anti-NB results by at least two mechanisms: an early effect by complement- and cell-mediated cytotoxicities and a delayed effect via an anti-idiotype network.17,37 The results in this phase II study likely reflect acute effects of 3F8. A possible role for anti-idiotypic antibodies is being assessed in our study (mentioned above) involving a more uniform population, viz, patients who receive 3F8/GM-CSF for consolidation of CR.


   NOTE ADDED IN PROOF
 
3F8/GM-CSF has been used in five more patients with primary refractory disease; four achieved CR in BM, and one came off study because of HAMA. Also, patient no. 30 (Table 2) achieved CR in BM after cycle 7.


   ACKNOWLEDGMENTS
 
Supported in part by the National Cancer Institute (grant nos. CA61017 and CA72868), Bethesda, MD; and the Robert Steel Foundation, the Katie’s Find A Cure Fund, and the Justin Zahn Fund, New York, NY.

GM-CSF was generously supplied by Immunex Corporation, Seattle, WA.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Cheung NKV, Saarinen UM, Neely JE, et al: Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells. Cancer Res 45: 2642-2649, 1985[Abstract/Free Full Text]

2. Schulz G, Cheresh DA, Varki NM, et al: Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma. Cancer Res 44: 5914-5920, 1984[Medline]

3. Kramer K, Gerald WL, Kushner BH, et al: Disialoganglioside GD2 loss following monoclonal antibody therapy is rare in neuroblastoma. Clin Cancer Res 4: 2135-2139, 1998[Abstract]

4. Yeh SDJ, Larson SM, Burch L, et al: Radioimmunodetection of neuroblastoma with iodine-131-3F8: Correlation with biopsy, iodine-131-metaiodobenzylguanidine and standard diagnostic modalities. J Nucl Med 32: 769-776, 1991[Abstract/Free Full Text]

5. Saarinen UM, Coccia PF, Gerson SL, et al: Eradication of neuroblastoma cells in vitro by monoclonal antibody and human complement: Method for purging autologous bone marrow. Cancer Res 45: 5969-5975, 1985[Medline]

6. Munn DH, Cheung N-KV: Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. Cancer Res 47: 6600-6605, 1987[Medline]

7. Munn DH, Cheung N-KV: Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. J Exp Med 170: 511-526, 1989[Abstract/Free Full Text]

8. Kushner BH, Cheung N-KV: GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood 73: 1936-1941, 1989[Abstract/Free Full Text]

9. Cheung N-KV, Walter EI, Smith-Mensah WH, et al: Decay-accelerating factor protects human tumor cells from complement-mediated cytotoxicity in vitro. J Clin Invest 8: 1122-1128, 1988

10. Cheung N-KV, Lazarus H, Miraldi FD, et al: Ganglioside GD2 specific monoclonal antibody 3F8: A phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol 5: 1430-1440, 1987[Abstract/Free Full Text]

11. Cheung N-KV, Kushner BH, Yeh SDJ, et al: 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: A phase II study. Int J Oncol 12: 1299-1306, 1998[Medline]

12. Cheung N-KV, Kushner BH, Cheung IY, et al: Anti-GD2 antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16: 3053-3060, 1998[Abstract/Free Full Text]

13. Guinan EC, Sieff CA, Oette DH, et al: A phase I/II trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia. Blood 76: 1077-1088, 1990[Abstract/Free Full Text]

14. Furman WL, Fairclough DL, Huhn RD, et al: Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy. J Clin Oncol 9: 1022-1028, 1991[Abstract]

15. Barker E, Mueller BM, Handgretinger R, et al: Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res 51: 144-149, 1991[Abstract/Free Full Text]

16. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11: 1466-1477, 1993[Abstract/Free Full Text]

17. Cheung N-KV, Cheung IY, Canete A, et al: Antibody response to murine anti-GD2 monoclonal antibodies: Correlation with patient survival. Cancer Res 54: 2228-2233, 1994[Abstract/Free Full Text]

18. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341: 1165-1173, 1999[Abstract/Free Full Text]

19. Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 327: 28-35, 1992[Medline]

20. Foulke RS, Marshall MH, Trotta PP, et al: In vitro assessment of the effects of granulocyte-macrophage colony-stimulating factor on primary human tumors and derived lines. Cancer Res 50: 6264-6267, 1990[Abstract/Free Full Text]

21. Neidhart JA: Hematopoietic colony-stimulating factors: Uses in combination with standard chemotherapeutic regimens and in support of dose intensification. Cancer 70: 913-920, 1992[Medline]

22. Tepper RI, Coffman RL, Leder P: An eosinophil-dependent mechanism for the antitumor effect of interleukin 4. Science 257: 548-551, 1992[Abstract/Free Full Text]

23. Sanderson CJ: Interleukin-5, eosinophils, and disease. Blood 79: 3101-3109, 1992[Free Full Text]

24. Lampson LA, Fisher CA, Whelan JP: Striking paucity of HLA-A, B, C and B2 microglobulin on human neuroblastoma cell lines. J Immunol 130: 2471-2478, 1983[Abstract]

25. Gross N, Carrel S, Beck D, et al: Cell adhesion molecules expression and modulation on human neuroblastoma cells. Prog Clin Biol Res 366: 293-299, 1991[Medline]

26. Cebon J, Dempsey P, Fox R, et al: Pharmacokinetics of human granulocyte-macrophage colony-stimulating factor using a sensitive immunoassay. Blood 72: 1340-1347, 1988[Abstract/Free Full Text]

27. Petros WP, Rabinowitz J, Stuart AR, et al: Disposition of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving high-dose chemotherapy and autologous bone marrow support. Blood 80: 1135-1140, 1992[Abstract/Free Full Text]

28. Peters WP, Stuart A, Affronti ML, et al: Neutrophil migration is defective during recombinant human granulocyte-macrophage colony-stimulating factor infusion after autologous bone marrow transplantation in human. Blood 72: 1310-1315, 1988[Abstract/Free Full Text]

29. Kushner BH, Wolden S, LaQuaglia MP, et al: Hyperfractionated low-dose radiotherapy (21 Gy) for high-risk neuroblastoma after intensive chemotherapy and surgery. J Clin Oncol 19: 2821-2828, 2001[Abstract/Free Full Text]

30. Handgretinger R, Baader P, Dopfer R, et al: A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother 35: 199-204, 1992[Medline]

31. Murray JL, Cunningham JE, Brewer H, et al: Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors. J Clin Oncol 6: 184-193, 1994[Medline]

32. Handgretinger R, Anderson K, Lang P, et al: A phase I study of human/mouse chimeric anti-ganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer 31A: 261-267, 1995

33. Frost JD, Hank JA, Reaman GH, et al: A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: A report of the Children’s Cancer Group. Cancer 80: 317-333, 1997[Medline]

34. Yu AL, Batova A, Alvarado C, et al: Usefulness of a chimeric anti-GD2 (ch14.18) and GM-CSF for refractory neuroblastoma: A POG phase II study. Proc Am Soc Clin Oncol 16: 513a, 1997 (abstr 1846)

35. Yu AL, Uttenreuther-Fischer MM, Huang CS, et al: Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol 16: 2169-2180, 1998[Abstract]

36. Ozkaynak MF, Sondel PM, Krailo MD, et al: Phase I study of chimeric human/murine anti-GD2 monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: A Children’s Cancer Group study. J Clin Oncol 18: 4077-4085, 2001[Abstract/Free Full Text]

37. Cheung N-KV, Guo H-F, Cheung IY: Correlation of anti-idiotype network with survival following anti-GD2 monoclonal antibody 3F8 therapy of stage 4 neuroblastoma. Med Pediatr Oncol 35: 635-637, 2000[Medline]

Submitted February 9, 2001; accepted June 26, 2001.




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I. Y. Cheung, M. S. Lo Piccolo, B. H. Kushner, and N.-K. V. Cheung
Early Molecular Response of Marrow Disease to Biologic Therapy Is Highly Prognostic in Neuroblastoma
J. Clin. Oncol., October 15, 2003; 21(20): 3853 - 3858.
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A. Garaventa, R. Luksch, M. S. L. Piccolo, E. Cavadini, P. G. Montaldo, M. R. Pizzitola, L. Boni, M. Ponzoni, A. Decensi, B. D. Bernardi, et al.
Phase I Trial and Pharmacokinetics of Fenretinide in Children with Neuroblastoma
Clin. Cancer Res., June 1, 2003; 9(6): 2032 - 2039.
[Abstract] [Full Text] [PDF]

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I. Y. Cheung, M. S. Lo Piccolo, B. H. Kushner, K. Kramer, and N.-K. V. Cheung
Quantitation of GD2 Synthase mRNA by Real-Time Reverse Transcriptase Polymerase Chain Reaction: Clinical Utility in Evaluating Adjuvant Therapy in Neuroblastoma
J. Clin. Oncol., March 15, 2003; 21(6): 1087 - 1093.
[Abstract] [Full Text] [PDF]

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