Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Drugs Future. Author manuscript; available in PMC 2010 October 27.
Published in final edited form as:
Drugs Future. 2010; 35(8): 665.
PMCID: PMC2964668

Anti-GD2 Strategy in the Treatment of Neuroblastoma


The prognosis for advanced neuroblastoma remains poor with high risk of recurrence after consolidation. Therapies based on monoclonal antibodies that specifically target disialoganglioside GD2 on tumor cells are improving treatment results for high-risk neuroblastoma. This article reviews the use of anti-GD2 antibodies either as monotherapy or as part of a larger and more complex treatment approach for advanced neuroblastoma. We review how anti-GD2 antibodies can be combined with other treatments or strategies to enhance their clinical effects. Tumor resistance and other problems that decrease the efficacy of anti-GD2 antibodies are discussed. Future developments in the area of anti-GD2 immunotherapies for neuroblastoma are also addressed.

A. Neuroblastoma

1. Significance, Standard of Care, Clinical Strategies

Neuroblastoma is the most common malignancy in infants, the most common extracranial solid tumor of childhood, and the third most common cancer in children (15). The average age at diagnosis is 17 months with 50–60% of patients having metastatic disease when diagnosed (68). Overall treatment has improved in children under 15 years of age with 5-year overall survival rates for newly diagnosed patients increasing from 52% in the 1970s to 69% in the last decade (9,10).

Despite advances in the treatment of low- to intermediate-risk neuroblastoma, outcomes for patients with advanced disease remain poor. Standard treatment for high-risk patients includes surgery, radiation, and/or myeloablative chemotherapy with autologous stem cell transplantation, followed by cis-retinoic acid (CRA). CRA, an anti-proliferative agent, when given following completion of chemotherapy has been shown to have an increased survival effect in patients with stage 4 disease (4,1112). With current standard therapy, most high risk patients achieve remission with no clinically evident disease (NED) status. However, complete eradication of tumor cells has remained elusive. Microscopic residual tumor cells (minimal residual disease) survive treatment and cause recurrent refractory disease. The 3-year event-free survival of these high risk patients remains as low as ~30% (4,6,1314). Fortunately, a recent COG randomized trial has shown that a combination of anti-GD2 antibody and cytokines in this setting can help prevent recurrence (15,16).

In this review, we examine several current strategies using monoclonal antibodies (mAbs) against the disialoganglioside GD2, and their derivatives, for the treatment of high risk neuroblastoma, either as primary therapy or as part of a multifaceted treatment approach, in clinical trials. We review the pitfalls of this treatment approach, including tumor resistance and the development of blocking antibodies that may interfere with mAb therapy. Finally, we look ahead at potential future therapies.

2. GD2-Importance, Rationale

Surface antigens expressed on neuroblastoma that have been used as targets for mAbs include the gangliosides GD2, GD3 and GM3, and the glycoproteins CD56 (NCAM), L1-CAM, GP58 and GP95 (17). GD2 is a disialoganglioside antigen that is expressed on tumors of neuroectodermal origin including neuroblastoma and melanoma (1819). These tumors express GD2 with relatively little heterogeneity between cells (2021). Patients with neuroblastoma were found to have significantly elevated free GD2 levels in serum compared with normal children and children with other tumors (20). Also, GD2 expression is not lost from the cell surface of neuroblastoma cells even when bound to antibody, unlike other tumor antigens described previously (21).

In normal tissues, GD2 expression on is largely limited to neurons, skin melanocytes, and peripheral pain fibers (22), making it well suited for targeted antitumor therapy. Recently, GD2 has been “ranked” 12th in priority of all clinical cancer antigens by an NCI workshop (23). In addition to neuroblastoma and melanoma, GD2 is expressed on some soft tissue sarcomas, osteosarcomas, and small cell lung cancers (24,18). In all, GD2+ diseases account for ~8% of all cancer deaths in the US (25).

GD2 has been used extensively as a target in mAb therapy and has been the primary target of antibody recognition in neuroblastoma. In 1984, a murine mAb (mAB126) was produced against cultured human neuroblastoma cells (LAN1). The original murine anti-GD2 mAbs described were 3F8, 14.18 and 14.G2a (1819). Clinical testing has been performed with 3F8, 14.G2a, and ch14.18 (the human-mouse chimeric variant of 14.18) in neuroblastoma and melanoma (2633).

B. Single Agent Antibodies

1. ADCC and CDC

An ideal anticancer agent would specifically target tumor cells and minimize injury to healthy cells (24). Monoclonal antibody (mAb) therapy creates specificity to tumor cells through its recognition of cell surface antigens found exclusively on tumor cells or that are found in much greater amounts on tumor cells compared to normal cells (3435). Currently, mAbs are in use in the detection, diagnosis, and treatment of neuroblastoma (14,3638). Antibodies can mediate destruction of tumor cells through several mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC). After the variable region of the antibody binds to antigen on the tumor cell, the Fc portion of the antibody can bind to the Fc receptor on monocytes, macrophages, neutrophils and/or natural killer (NK) cells and stimulate tumor cell lysis via ADCC (3940).

In addition, complement-dependent cytotoxicity (CDC) may be induced after an antibody binds to the tumor cell surface (24). However, dose limiting toxicities (DLT) caused by anti-GD2 mAb do occur and include fever, chills, anaphylactoid reactions most likely from cytokine and complement activation, and transient neuropathic pain, which are controllable with analgesics. These toxicities are mostly likely the result of mAb recognition of GD2 on peripheral pain fibers and complement deposition (4042,22,29).

2. 3F8 Clinical Testing

The first mAb tested in clinical trials was the anti-GD2 mAb 3F8 (26,4346). In the initial Phase I and II trials using 3F8 in patients with stage 4 neuroblastoma, there was no significant antitumor effect on bulky disease but some response in microscopic bone marrow disease (17,4750). Side effects included pain most commonly, hypertension, hypotension, fever, vomiting, diarrhea, and urticaria. Pain can be dose limiting and has been attributed to antibody recognition of peripheral pain fibers expressing GD2 (4042). Also, human antimouse antibodies (HAMA) can develop in patients treated with 3F8. As these neutralize the function of 3F8, development of HAMA has resulted in termination of therapy (51). 3F8 has been shown to activate tumor cell destruction by both CDC and ADCC in vitro (5253).

3. 14.G2a

The 14.18 antibody is a separate IgG3 murine mAb targeted to the GD2 antigen (18). In an effort to enhance ADCC, a class switch variant called 14.G2a has also been prepared (54). The 14.G2a antibody activates complement and mediates ADCC with monocytes, neutrophils, NK cells, and lymphokine-activated killer (LAK) cells (5556). The 14.G2a antibody has undergone clinical testing both as single-agent therapy and in combination approaches. Its toxicities and induction of HAMA responses were similar to that seen with 3F8.

4. Ch14.18 Clinical Testing

A human-mouse chimeric form of the 14.18 murine anti-GD2 mab, designated ch14.18, was subsequently created to reduce the immunogenicity associated with the murine antibody (Fig. 1). The chimeric antibody is less immunogenic and is more effective than 14.G2a in mediating lysis of neuroblastoma cells with NK cells (57). The ch14.18 antibody has undergone clinical testing as a single-agent therapy. Simon et al. have published their results using standard induction treatment (chemotherapy with autologous stem cell rescue) for children and infants with stage 4 neuroblastoma followed by consolidation with chimeric 14.18 antibody for 5 days every 2 months, versus 12 months of oral maintenance chemotherapy or no further therapy (58). In patients <1 year old, there was no significant difference in event-free survival or overall survival in the three consolidation groups, with an overall survival of >90%. In patients >1 year old, the 3-year overall survival of ch14.18 treatment was superior to maintenance therapy or no additional therapy (P = 0.018) (59), although there was no difference in event free survival.

Figure 1
Monoclonal Antibodies and Immunocytokines. (a) A chimeric monoclonal antibody (mAb) combines the constant region of a human antibody with the variable domain of a murine antibody. The antigen specificity is conferred by the murine variable domain. (b) ...

5. Hu14.18K322A Clinical Testing

A Phase I clinical trial is now underway at St. Jude Hospital using a novel hu14.18K322A anti-GD2 mAb, which was made using the same variable region as the ch14.18 mAb. However, this mAb has 3 major differences from the ch14.18 mAb. First, it is a humanized, not chimeric, mAb and thus could be less immunogenic with less allergic toxicity than ch14.18. Second, there is a single amino acid switch, from K to A at position 322 in the Fc region, which nearly abrogates complement activation, hopefully resulting in less neuropathic toxicity than ch14.18. Third, this mAb is produced in the YB2/O cell line, rather than CHO or NS/O lines, eliminating the normal fucosylation of the Fc region, and hopefully augmenting interaction with FcRs to increase ADCC (60). Thus, this novel hu14.18K322A is designed to cause less allergic reactions, less complement dependent toxicity, and more ADCC-mediated antitumor effects than ch14.18.

C. Antibodies Combined with other Agents

1. Antibody plus ADCC-Augmenting Cytokines

As the mechanisms of mAb-based tumor cell lysis were discovered, it was evident that the antibody must accomplish three separate jobs to kill a tumor cell. First, the antibody must recognize and bind to the tumor cell. Second, it must bind long enough and avoid internalization to adequately signal immune effector mechanisms. Third, the activated immune effector cells or effector proteins must be able to create a destructive signal (24). Since mAb-mediated tumor cell destruction relies on ADCC and/or CDC to kill tumor cells, strong effector functions are required. However, effector function, particularly ADCC, is often compromised in cancer patients due to immune suppression from metastatic cancer and/or chemotherapy (17,53,61). It is thought that the addition of cytokines that activate cells to mediate enhanced ADCC to mAb therapy will augment effector cell function and improve the overall antibody therapy efficacy (24).

a. 14.G2a + IL-2 Trial

Interleukin 2 (IL-2) is a strong pro-inflammatory cytokine with effects on both innate immunity, increasing the number and activation state of NK cells, and adaptive immunity, stimulating antigen-specific T cells (6263). A Phase I trial through the Children’s Cancer Group involved 33 patients. IL-2 was administered by three 96 hr infusions on days 1, 8, and 15 over consecutive weeks and 14.G2a was given as a daily 2 h infusion between days 9–13 (64). The treatment timing sought to take advantage of IL-2 induced lymphocytosis and maximal NK cell cytotoxic activity seen in several previously conducted in vitro analyses (65). One patient had a partial response with a 70% size decrease in an abdominal tumor facilitating complete resection. Three additional patients had a transient reduction in microscopic bone marrow disease but no overall reduction in tumor burden. Serum samples from these patients were found to have sufficient levels of 14.G2a to result in ADCC of GD2-positive tumor cells in in vitro assays (66). HAMA responses were also noted.

b. Ch14.18 + GM-CSF + IL-2 + CRA Pilot Trial

Testing of ch14.18 in refractory neuroblastoma included co-administration of GM-CSF in studies done by the Pediatric Oncology Group (67,68). Also, the Children’s Cancer Group conducted a Phase I clinical trial of ch14.18 with GM-CSF in children with neuroblastoma immediately after hematopoietic stem cell transplant (69). Results of this trial determined the MTD of ch14.18 in combination with GM-CSF to be 40 mg/m2/day for 4 days in the early post-transplant period. A subsequent Phase I study found the MTD of ch14.18 to be 25 mg/m2/d for 4 days given concurrently with 4.5 × 106 U/m2/d of IL-2 for 4 days with alternating cycles of IL-2 and GM-CSF. Though two patients experienced DLTs from ch14.18 and IL-2, this combination was deemed tolerable in the early post-transplant period. This study also found that cis-RA can be safely administered between courses of ch14.18 and cytokines (70).

c. Phase III Neuroblastoma Ch14.18 + GM-CSF + IL-2 + CRA Trial

Preliminary data led to the design of the Children’s Oncology Group (COG) Phase III trial, ANBL0032, which prospectively examined this ch14.18 + GM-CSF + IL-2 + CRA combination therapy in patients after myeloablative chemotherapy and autologous stem cell rescue. CRA was added to the regimen because it was shown previously in a Phase III clinical trial to improve overall survival in patients with stage 4 neuroblastoma (4). Following autologous transplant, patients were randomized to receive CRA alone or CRA in combination with ch14.18 and GM-CSF (in courses 1, 3 and 5) and IL-2 (in courses 2 and 4) (16).

From 226 patients with high-risk neuroblastoma, the results showed a two-year event-free survival of 66% in the immunotherapy group versus 46% in the standard treatment group (p=0.0115). Overall survival at two years was 86% for the immunotherapy group versus 75% for the standard treatment group (p= 0.016). The results from this phase III trial have been recently reported (16).

This study shows a substantive increase in survival for high risk neuroblastoma. It is the first clinical trial to document that a combination of an anti-cancer mAb with ADCC-augmenting cytokines is an effective anticancer therapy. Also, it is the first time an antibody targeting a non-protein antigen (as GD2 is a glycolipid) has proven to be effective for immunotherapy of cancer. The 20% improvement in 2-year prevention of relapse for children with neuroblastoma receiving the experimental immunotherapy represents an advance in treatment that is being regarded now as the treatment of choice for high risk patients that achieve remission, in order to decrease the chance of relapse (16).

This study also shows the use of a monoclonal antibody combined with cytokines (GM-CSF and IL-2) to enhance antibody dependent cell-mediated cytotoxicity (ADCC) having made an impact on increasing survival in neuroblastoma in a minimal residual disease setting. Other monoclonal antibodies also mediate ADCC (Rituxan, Erbitux, Herceptin), but have yet to be tested with cytokines in a minimal residual disease setting. This trial may portend future clinical trials testing cytokine combinations in more common malignancies that are currently treated with monoclonal antibodies (16).

d. 3F8 plus β-glucan

3F8 therapy is enhanced in mice when used in combination with the glucose polymer β-glucan (71). β-glucan sugars act as strong signals to the innate immune system, are well tolerated, and have been shown to stimulate TNF-α secretion and ADCC mediated by NK cells, monocytes, and neutrophils (7276). 3F8 mAb binds to a tumor cell and coats tumor cells with iC3b. Soluble β-glucans can be used to prime CR3, the iC3b receptor, on the leukocytes, and cause dual ligation of the CR3 receptor on leukocytes to both iC3b and soluble β-glucan, which enhances tumor cytotoxicity (71,72). In vivo, oral or intraperitoneal β-glucan has been shown to be effective against neuroblastoma in mice. In nude mice bearing human neuroblastoma tumors, β-glucan and 3F8 mAb therapy resulted in near-complete tumor resolution while either agent alone had less effect. Survival was also increased compared with control animals and this effect was lost when tested on GD2-negative tumors (44,77). The use of β-glucan in conjunction with 3F8 is currently in clinical investigation.

D. Conjugated Antibodies

1. Antibodies Linked to Toxic Agents (Toxins, Chemotherapeutics, Radionuclides)

Antibodies are fairly easy to manufacture and can be linked to toxic agents. Conjugating mAbs to agents for selective delivery to tumor cells has included toxins, chemotherapeutic agents, radioactive isotopes, and immunological agents. Preclinical and some clinical work have been performed with these agents.

2. Radioimmunoconjugates

Radiolabeled mAbs have been used for both disease detection and targeted treatment of a variety of adult cancers but very few childhood tumors. However, radioimmunotherapy is attractive in neuroblastoma because of extensive studies on GD2 directed mAbs and because its tendency to be radiosensitive (78). The only widely studied radio-labeled mAb for treatment of neuroblastoma is 131I-labelled 3F8. A Phase I dose-escalation study performed at Memorial Sloan-Kettering Cancer Center (MSKCC, New York) enrolled 23 patients with refractory stage 4 neuroblastoma. Out of ten patients evaluable, two had complete response (CR) of bone marrow disease and two had a partial response (PR) of soft-tissue disease (78). Based on these results, 131I-labelled 3F8 was added to a multimodal treatment regimen under study at MSKCC for children with high-risk neuroblastoma (79).

3. Immunocytokines (ICs) - Antibodies Linked to Cytokines

a. ch14.18-IL2

The ch14.18-IL2 is an immunocytokine (IC) formed by linking IL-2 to the carboxyl end of the constant region of the chimeric mouse–human IgG1 ch14.18 mAb (8082). Preclinical data in mice show that treatment with ch14.18-IL2 is far superior to comparable doses of ch14.18 mAb combined with IL-2 in mediating antitumor effects. In general, ADCC depends on the number and function of Fc receptors (FcR) on effector cells including activated NK cells (83,24,61,84). However, activated NK cells also have augmented IL-2 receptor (IL-2R) expression (85) leading to a dramatic in vitro response to IL-2 (86). In mouse models, the IL-2 component of this IC can activate NK cells without FcR, through their IL-2R (87). Thus, it is thought that effector cell binding to tumor is mediated in T-cells via IL-2Rs and in NK cells via FcRs and IL-2Rs (82,88). Data suggest that ch14.18-IL-2 could function as both a T-cell inducing vaccine as well as an activator of NK mediated ADCC. These data provided the basis for initiating clinical testing of this 14.18 based IC molecule as therapy for neuroblastoma (83) using an immunocytokine based on the humanized, rather than chimeric, form of the mAb; this IC is hu14.18-IL2.

b. hu14.18-IL2

i. Preclinical Development

When murine (14.G2a) or chimeric (ch14.18) anti-GD2 IgG mAbs are injected intravenously (IV) in mice, half-life is 2–5 days (29,62). In contrast, the half-life of the ch14.18-IL-2 and hu14.18-IL2 is only ~4hrs (89) when injected intravenously into mice. These data led to hu14.18-IL2 being given frequently (daily) to maintain both IL-2 and hu14.18 in vivo activity (83).

ii. Phase I Testing in Neuroblastoma

The Children’s Oncology Group has completed a Phase I trial using hu14.18-IL2 in 27 pediatric patients with recurrent neuroblastoma using four courses of hu14.18-IL2 for patients with stable disease (90). The MTD was 12 mg/m2/day with dose limiting toxicities (DLTs) of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. No CR or PR was noted, but three patients had clinical changes suggestive of antitumor activity with radiographic and bone marrow response. Immune activation was noted with elevated sIL-2Rα and lymphocytosis. All toxicities were reversible, and there were no treatment-related deaths.

iii. Phase II Study

A Phase II study (COG-ANBL0322) of hu14.18-IL2 in children with recurrent or refractory neuroblastoma was designed to evaluate the clinical antitumor activity and in vivo immunological effects of hu14.18-IL2. Also, this study sought to differentiate between patients with bulky disease and patients with minimal evaluable neuroblastoma. Patients received 3 daily IV doses of 12.0 mg/M2/d hu14.18-IL2 in each of 4 monthly courses (91). Fifteen patients had disease measurable by standard radiographical criteria (stratum-1) and 24 patients had disease evaluable only by meta-iodobenzylguanidine (MIBG) scanning and/or bone marrow (BM) histology (stratum-2). Responses were confirmed by independent radiological review and immunocytochemical (ICC) evaluation of the bone marrow.

No responses were seen in the 15 stratum-1 patients. In the 24 stratum-2 patients, 5 showed CR (MIBG and BM/ICC resolution). These response data support the conclusion that this agent and regimen have clinical activity in stratum-2 but not in stratum-1 patients (92). As all patients in this study had recurrent/refractory disease to prior multi-modality therapy, these responses are of interest to pediatric oncologists (91).

E. Anti-Idiotypic Antibodies

1. Mechanism of Tumor Resistance to Anti-GD2 Ab (HAMA, HACA, HAHA)

A problem with mouse mAb therapy has been the development of blocking antibodies to the mAb itself, called a HAMA (human anti-mouse antibody) response (80,57). The development of a HAMA response has been detected within 7 days of treatment and can neutralize any further treatments with the mouse anti-GD2 antibody (83,80). This led to the development of increasingly humanized versions of these mAbs. Chimeric antibodies have linked the GD2 specific variable ends of the immunoglobulin light and heavy chains from the mouse antibody to the human constanst regions of the immunoglobulin light and heavy chains from the human antibody to create a less immunogenic mAb. Unfortunately, human “antichimeric” antibody (HACA) responses can still be detected (80,69).

The current humanized mAb, hu14.18, was developed retaining only the complementarity-determining regions (CDRs) of the original mouse antibody. It is ~98% human amino acid sequence (Fig. 1) (83,80,65). This humanized form of IC, hu14.18-IL2, was made with hopes of reducing immunogenicity of the IC in patients and has been studied in recently completed Phase I and II trials (80,90). The humanized mAb making the hu14.18-IL2 less immunogenic typically does not stimulate a neutralizing HACA or human antihumanized antibody (HAHA) response (24).

2. Anti–IC Antibodies and Antibody-Response Networks

Normally, the HAMA response inhibits antitumor effect. However, a HAMA response has been associated with increased antitumor effect that was also associated with enhanced survival (12). Current thinking suggests that an antibody-response network mechanism may be responsible for providing antitumor benefit. The antigen binding component of an anti-GD2 mAb (Ab-1) serves as an antigen for another antibody (Ab-2) generated in response to Ab-1 treatment. This binding region of Ab-2 may be “immunologically similar” to the GD2 antigen itself (as both bind to the antigen binding portion of the anti-GD2 mAb) and may serve as an additional antigen source for induction of a third antibody (Ab-3). Ab-3 in certain cases can bind to GD2 as well as Ab-2 and can generate antitumor responses similar to those elicited by Ab-1 (24,93,94).

In patients receiving 3F8 antibody, presence of Ab-3 was a predictor of overall survival (6,94). Ab-3 is not seen in all patients. Anti-idiotypic antibodies (Ab-2) have been used as an antigen source in clinical trials (6,9597). Also, similar to Ab-2, peptide mimics that bind to the therapeutic Ab-1 have been used in place of GD2 or Ab-2 molecule in an effort to induce an active antitumor response following vaccination (98,99). Currently, efforts at inducing ADCC are focused on patients entering remission, which typically requires intense immunosuppressive treatment to achieve. Therefore, as of now, the paradigm of immunotherapy is to avoid the HACA/HAMA (Ab-2) response.

F. T-cell Engineering in the Treatment of Neuroblastoma

T-cell activation and tumor-specific memory responses have been shown in response to mAbs in animal models and clinical settings (100). T-cell cytotoxicity can be enhanced through manipulation of the T-cell receptor (TCR) to redirect its specificity toward tumor antigens (101). T cells have been genetically altered to express chimeric TCRs consisting of a variable domain of an anti-GD2 antibody linked to a cytoplasmic signaling domain. Engagement of the TCR complex initiates cytotoxic effector function and release of pro-inflammatory cytokines including GM-CSF and IFN-γ upon incubation with GD2-positive tumor cells. These modified T cells mediate antitumor killing with minimal effects on GD2-negative targets (102).

Isolation of CD8+ T cells with altered TCR specificity from plasmids encoding engineered antigen receptors has been shown in human patients (103,104). Incorporation of DNA encoding the novel antigen receptors has been achieved via uptake of naked plasmid DNA by electroporation and retrovirus transfection (102,105). Typically, infusions of autologous tumor-specific T cells had half-lives of 1–42 days with minimal toxicity. Although this approach has been used more extensively for leukemia and lymphoma, human clinical trials targeting neuroblastoma are also under way (104108). Patients who undergo stem cell transplantation require months to regenerate a functional immune system. Thus, the infusion of large numbers of tumor-specific effector T cells is an attractive alternative to waiting for an autologous immune response, especially in a minimal residual disease setting.

G. Summary

Current conventional therapy of high-risk neuroblastoma (surgery, radiation therapy and multi-agent chemotherapy) can put most children into remission. However, the majority of these patients eventually succumb to recurrent or refractory disease. The current strategy for treatment development is to utilize separate therapeutic approaches for patients in remission but harboring minimal residual disease. The use of anti-GD2 mAbs in this setting has been a promising approach under investigation. Preclinical data using these mAbs show strong anti-tumor effects in the minimal residual disease setting, and antitumor efficacy preclinically can be enhanced by using cytokines that stimulate ADCC. This has potential clinical implications for patients, who have already undergone conventional surgery, radiation and/or chemotherapy, and who are in remission but suspected to carry minimal residual disease. A recent Phase III trial of this approach by the Children’s Oncology Group has shown a 20% increase in event-free survival after two years. Novel approaches, using genetically engineered mAb derivatives, alone or combined with other agents, are even more effective in preclinical testing. Clinical trials of these concepts are underway to determine how best to integrate these approaches into an overall multi-modality treatment that can provide improved long-term disease free survival.


This work was supported by NIH-NCI grants CA87025 and CA32685, a grant from the Midwest Athletes Against Childhood Cancer (MACC) Fund, and support from The Crawdaddy Foundation.


1. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am. 2008 Feb;55(1):97–120. x. Review. [PMID: 18242317] [PubMed]
2. Ishola TA, Chung DH. Neuroblastoma. Surg Oncol. 2007 Nov;16(3):149–156. Epub 2007 Oct 31. Review. [PMID: 17976976] [PubMed]
3. Brodeur GM, Maris JM. Neuroblastoma. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric Oncology. Philadelphia: Lippincott; 2002. pp. 895–938.
4. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP. Children's Cancer Group. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med. 1999 Oct 14;341(16):1165–1173. [PMID: 10519894] [PubMed]
5. Brodeur GM. Significance of intratumoral genetic heterogeneity in neuroblastomas. Med Pediatr Oncol. 2002 Feb;38(2):112–113. [PMID: 11813176] [PubMed]
6. Cheung NK, Kushner BH, Kramer K. Monoclonal antibody-based therapy of neuroblastoma. Hematol Oncol Clin North Am. 2001 Oct;15(5):853–866. Review. [PMID: 11765377] [PubMed]
7. Cheung NK, et al. Treatment of advanced stage neuroblastoma. In: Reghavan D, editor. Principles and Practice of Genitourinary Oncology. Lippincott, Williams, and Wilkins; 1997. pp. 1101–1111.
8. Ater JL. Neuroblastoma. In: Behrman RE, Kliegman RM, Jenson HA, editors. Behrman: Nelson Textbook of Pediatrics. 17th edn. Saunders; 2004. pp. 1709–1711.
9. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan–Feb;57(1):43–66. [PMID: 17237035] [PubMed]
10. Ries LAG, et al. SEER Cancer Statistics Review, 1975–2004. Bethesda, MD: National Cancer Institute; 2007., based on November 2006 SEER data submission, posted to the SEER Web site, 2007.
11. Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, Stram DO, Perez C, Haase GM, Matthay KK. Children's Cancer Group study. Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective. J Clin Oncol. 2000 Mar;18(6):1260–1268. [PMID: 10715296] [PubMed]
12. Kushner BH, LaQuaglia MP, Bonilla MA, Lindsley K, Rosenfield N, Yeh S, Eddy J, Gerald WL, Heller G, Cheung NK. Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol. 1994 Dec;12(12):2607–2613. [PMID: 7527454] [PubMed]
13. Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, Klingebiel T, Kremens B, Schilling FH, Schrappe M, Simon T, Hero B. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol. 2005 Sep;6(9):649–658. [PMID: 16129365] [PubMed]
14. Franks LM, Bollen A, Seeger RC, Stram DO, Matthay KK. Neuroblastoma in adults and adolescents: an indolent course with poor survival. Cancer. 1997 May 15;79(10):2028–2035. [PMID: 9149032] [PubMed]
15. Yu A, Gilman A, Ozkaynak F, Kletzel M, Castleberry R, Kretschmar C, Cohn S, Shimada H, Hoh CK, Sondel PM, Wiernikowski S, Bickert P, Seeger R, Reynolds CP, Matthay KK, Lalonde D, Shulkin B, London W, Frierdich S, Maloney A. COG ANBL0032. A Phase III trial of ch14.18 mAb plus IL2 plus GMCSF for children with high risk neuroblastoma following ASCT. COG protocol, open. 2001 Dec. Available on COG website, and NCI-PDQ.
16. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman S, Chen H, Smith M, Anderson B, Villablanca J, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM. Chimeric Anti-GD2 Antibody with GM-CSF, IL2 and 13-cis Retinoic Acid for High-risk Neuroblastoma: A Children’s Oncology Group (COG) Phase 3 Study. NEJM. In press. [PMC free article] [PubMed]
17. Cheung NK, Sondel PM. Neuroblastoma immunology and immunotherapy. In: Cohn S, Cheung NK, editors. Neuroblastoma. Springer Press; 2005. pp. 223–242.
18. Mujoo K, Cheresh DA, Yang HM, Reisfeld RA. Disialoganglioside GD2 on human neuroblastoma cells: target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. Cancer Res. 1987 Feb 15;47(4):1098–1104. [PMID: 3100030] [PubMed]
19. Cheung NK, Saarinen UM, Neely JE, Landmeier B, Donovan D, Coccia PF. Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells. Cancer Res. 1985 Jun;45(6):2642–2649. [PMID: 2580625] [PubMed]
20. Schulz G, Cheresh DA, Varki NM, Yu A, Staffileno LK, Reisfeld RA. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 1984 Dec;44(12 Pt 1):5914–5920. [PMID: 6498849] [PubMed]
21. Kramer K, Gerald WL, Kushner BH, Larson SM, Hameed M, Cheung NK. Disialoganglioside G(D2) loss following monoclonal antibody therapy is rare in neuroblastoma. Clin Cancer Res. 1998 Sep;4(9):2135–2139. [PMID: 9748131] [PubMed]
22. Svennerholm L, Boström K, Fredman P, Jungbjer B, Lekman A, Månsson JE, Rynmark BM. Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord. Biochim Biophys Acta. 1994 Sep 15;1214(2):115–123. [PMID: 7918590] [PubMed]
23. Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009 Sep 1;15(17):5323–5337. [PMID: 19723653] [PubMed]
24. Sondel PM, Hank JA. Antibody-directed, effector cell-mediated tumor destruction. Hematol Oncol Clin North Am. 2001 Aug;15(4):703–721. [PMID: 11676280] [PubMed]
25. American Cancer Society. Cancer Facts and Figures. Atlanta, GA: ACS publications; 2004.
26. Cheung NK, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, Spitzer T, Strandjord SE, Coccia PF, Berger NA. Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol. 1987 Sep;5(9):1430–1440. [PMID: 3625258] [PubMed]
27. Cheung NK, Kushner BH, Cheung IY, Kramer K, Canete A, Gerald W, Bonilla MA, Finn R, Yeh SJ, Larson SM. Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol. 1998 Sep;16(9):3053–3060. [PMID: 9738575] [PubMed]
28. Handgretinger R, Baader P, Dopfer R, Klingebiel T, Reuland P, Treuner J, Reisfeld RA, Niethammer D. A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother. 1992;35(3):199–204. [PMID: 1638557] [PubMed]
29. Yu AL, Uttenreuther-Fischer MM, Huang CS, Tsui CC, Gillies SD, Reisfeld RA, Kung FH. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol. 1998 Jun;16(6):2169–2180. [PMID: 9626218] [PubMed]
30. Handgretinger R, Anderson K, Lang P, Dopfer R, Klingebiel T, Schrappe M, Reuland P, Gillies SD, Reisfeld RA, Neithammer D. A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer. 1995;31A(2):261–267. [PMID: 7718335] [PubMed]
31. Murray JL, Cunningham JE, Brewer H, Mujoo K, Zukiwski AA, Podoloff DA, Kasi LP, Bhadkamkar V, Fritsche HA, Benjamin RS, et al. Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors. J Clin Oncol. 1994 Jan;12(1):184–193. [PMID: 8270976] [PubMed]
32. Saleh MN, Khazaeli MB, Wheeler RH, Dropcho E, Liu T, Urist M, Miller DM, Lawson S, Dixon P, Russell CH, et al. Phase I trial of the murine monoclonal anti-GD2 antibody 14G2a in metastatic melanoma. Cancer Res. 1992 Aug 15;52(16):4342–4347. [PMID: 1643631] [PubMed]
33. Saleh MN, Khazaeli MB, Wheeler RH, Allen L, Tilden AB, Grizzle W, Reisfeld RA, Yu AL, Gillies SD, LoBuglio AF. Phase I trial of the chimeric anti-GD2 monoclonal antibody ch14.18 in patients with malignant melanoma. Hum Antibodies Hybridomas. 1992 Jan;3(1):19–24. [PMID: 1576319] [PubMed]
34. Stephenson J. Reengineered monoclonal antibodies step up to the plate in cancer studies. JAMA. 1995 Dec 20;274(23):1821–1822. [PMID: 7500516] [PubMed]
35. Sondel PM, Hank JA, Gan J, Neal Z, Albertini MR. Preclinical and clinical development of immunocytokines. Curr Opin Investig Drugs. 2003 Jun;4(6):696–700. [PMID: 12901228] [PubMed]
36. Jurcic JG, Scheinberg DA, Houghton AN. Monoclonal antibody therapy of cancer. Cancer Chemother Biol Response Modif. 1997;17:195–216. Review. No abstract available. [PMID: 9551215] [PubMed]
37. Moss TJ, Reynolds CP, Sather HN, Romansky SG, Hammond GD, Seeger RC. Prognostic value of immunocytologic detection of bone marrow metastases in neuroblastoma. N Engl J Med. 1991 Jan 24;324(4):219–226. [PMID: 1985243] [PubMed]
38. Seeger RC, Reynolds CP, Gallego R, Stram DO, Gerbing RB, Matthay KK. Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study. J Clin Oncol. 2000 Dec 15;18(24):4067–4076. [PMID: 11118468] [PubMed]
39. Colucci F, Caligiuri MA, Di Santo JP. What does it take to make a natural killer? Nat Rev Immunol. 2003 May;3(5):413–425. [PMID: 12766763] [PubMed]
40. Lammie GA, Cheung NKV, Gerald W, et al. Ganglioside GD2 expression in the human nervous system and in neuroblastomas - an immunohistochemical study. International Journal of Oncology. 1993;3:909–915. [PubMed]
41. Xiao WH, Yu AL, Sorkin LS. Electrophysiological characteristics of primary afferent fibers after systemic administration of anti-GD2 ganglioside antibody. Pain. 1997 Jan;69(1–2):145–151. [PMID: 9060025] [PubMed]
42. Yuki N, Yamada M, Tagawa Y, Takahashi H, Handa S. Pathogenesis of the neurotoxicity caused by anti-GD2 antibody therapy. J Neurol Sci. 1997 Aug;149(2):127–130. [PMID: 9171318] [PubMed]
43. Kushner BH, Kramer K, LaQuaglia MP, Cheung NK. Curability of recurrent disseminated disease after surgery alone for local-regional neuroblastoma using intensive chemotherapy and anti-G(D2) immunotherapy. J Pediatr Hematol Oncol. 2003 Jul;25(7):515–519. [PMID: 12847316] [PubMed]
44. Cheung NK, Modak S. Oral (1-->3),(1-->4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma. Clin Cancer Res. 2002 May;8(5):1217–1223. [PMID: 12006541] [PubMed]
45. Sondel PM, Gillies SD. Immunocytokines for Cancer Immunotherapy. In: Morse MA, Clay TM, Lyerly HK, editors. Handbook of Cancer Vaccines. Humana Press; 2002. pp. 341–358.
46. Yeh SD, Larson SM, Burch L, Kushner BH, Laquaglia M, Finn R, Cheung NK. Radioimmunodetection of neuroblastoma with iodine-131-3F8: correlation with biopsy, iodine-131-metaiodobenzylguanidine and standard diagnostic modalities. J Nucl Med. 1991 May;32(5):769–776. [PMID: 1902508] [PubMed]
47. Cheung NK, Kushner BH, Yeh SD, Larson SM. 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: a phase II study. Int J Oncol. 1998 Jun;12(6):1299–1306. [PMID: 9592190] [PubMed]
48. Cheung NK. Monoclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep. 2000 Nov;2(6):547–553. [PMID: 11122891] [PubMed]
49. Cheung IY, Lo Piccolo MS, Kushner BH, Cheung NK. Early molecular response of marrow disease to biologic therapy is highly prognostic in neuroblastoma. J Clin Oncol. 2003 Oct 15;21(20):3853–3858. [PMID: 14551304] [PubMed]
50. Cheung IY, Lo Piccolo MS, Kushner BH, Kramer K, Cheung NK. Quantitation of GD2 synthase mRNA by real-time reverse transcriptase polymerase chain reaction: clinical utility in evaluating adjuvant therapy in neuroblastoma. J Clin Oncol. 2003 Mar 15;21(6):1087–1093. [PMID: 12637475] [PubMed]
51. Kushner BH, Kramer K, Cheung NK. Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol. 2001 Nov 15;19(22):4189–4194. [PMID: 11709561] [PubMed]
52. Cheung NK, Walter EI, Smith-Mensah WH, Ratnoff WD, Tykocinski ML, Medof ME. Decay-accelerating factor protects human tumor cells from complement-mediated cytotoxicity in vitro. J Clin Invest. 1988 Apr;81(4):1122–1128. [PMID: 2450893] [PMC free article] [PubMed]
53. Kushner BH, Cheung NK. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood. 1989 May 15;73(7):1936–1941. [PMID: 2653466] [PubMed]
54. Mujoo K, Kipps TJ, Yang HM, Cheresh DA, Wargalla U, Sander DJ, Reisfeld RA. Functional properties and effect on growth suppression of human neuroblastoma tumors by isotype switch variants of monoclonal antiganglioside GD2 antibody 14.18. Cancer Res. 1989 Jun 1;49(11):2857–2861. [PMID: 2720646] [PubMed]
55. Saarinen UM, Coccia PF, Gerson SL, Pelley R, Cheung NK. Eradication of neuroblastoma cells in vitro by monoclonal antibody and human complement: method for purging autologous bone marrow. Cancer Res. 1985 Nov;45(11 Pt 2):5969–5975. [PMID: 2414004] [PubMed]
56. Munn DH, Cheung NK. Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma. Cancer Res. 1987 Dec 15;47(24 Pt 1):6600–6605. [PMID: 3499978] [PubMed]
57. Barker E, Mueller BM, Handgretinger R, Herter M, Yu AL, Reisfeld RA. Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res. 1991 Jan 1;51(1):144–149. [PMID: 1988079] [PubMed]
58. Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Niethammer D, Berthold F. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol. 2004 Sep 1;22(17):3549–3557. [PMID: 15337804] [PubMed]
59. Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Niethammer D, Berthold F. Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14.18 consolidation therapy. Klin Padiatr. 2005 May–Jun;217(3):147–152. [PMID: 15858706] [PubMed]
60. Ito A, Ishida T, Yano H, Inagaki A, Suzuki S, Sato F, Takino H, Mori F, Ri M, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer Immunol Immunother. 2009 Aug;58(8):1195–1206. Epub 2008 Dec 2. [PMID: 19048251] [PubMed]
61. Hank JA, Robinson RR, Surfus J, Mueller BM, Reisfeld RA, Cheung NK, Sondel PM. Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2. Cancer Res. 1990 Sep 1;50(17):5234–5239. [PMID: 2386933] [PubMed]
62. Mulé JJ, Yang JC, Afreniere RL, Shu SY, Rosenberg SA. Identification of cellular mechanisms operational in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2. J Immunol. 1987 Jul 1;139(1):285–294. [PMID: 3108401] [PubMed]
63. Sondel PM, Hank JA. Combination therapy with interleukin-2 and antitumor monoclonal antibodies. Cancer J Sci Am. 1997 Dec;3 Suppl 1:S121–S127. Review. [PMID: 9457407] [PubMed]
64. Frost JD, Hank JA, Reaman GH, Frierdich S, Seeger RC, Gan J, Anderson PM, Ettinger LJ, Cairo MS, Blazar BR, Krailo MD, Matthay KK, Reisfeld RA, Sondel PM. 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. 1997 Jul 15;80(2):317–333. [PMID: 9217046] [PubMed]
65. Hank JA, Albertini MR, Sondel PM. Monoclonal antibodies, cytokines and fusion proteins in the treatment of malignant disease. In: Pinedo HM, Longo DL, Chabner BA, editors. Cancer Chemotherapy and Biological Response Modifiers Annual 18. Elsevier Science; 1999. pp. 210–222. [PubMed]
66. Hank JA, Surfus J, Gan J, Chew TL, Hong R, Tans K, Reisfeld R, Seeger RC, Reynolds CP, Bauer M, et al. Treatment of neuroblastoma patients with antiganglioside GD2 antibody plus interleukin-2 induces antibody-dependent cellular cytotoxicity against neuroblastoma detected in vitro. J Immunother Emphasis Tumor Immunol. 1994 Jan;15(1):29–37. [PMID: 8110728] [PubMed]
67. Yu AL, Batova A, Alvarado C, Rao VJ, Castelberry RP. Usefulness of a chimeric anti-GD2 (ch14.18) and GM-CSF for refractory neuroblastoma: a POG phase II study. Proc. Am. Soc. Clin. Oncol. 1997;16:1846.
68. Yu AL, Uttenreuther MM, Kamps A, Batova A, Reisfeld RA. Combined use of a human-mouse chimeric anti-GD2 (ch14.18) and GM-CSF in the treatment of refractory neuroblastoma. Antibody Immunoconjugates Radiopharmaceuticals. 1995;8:12.
69. Ozkaynak MF, Sondel PM, Krailo MD, Gan J, Javorsky B, Reisfeld RA, Matthay KK, Reaman GH, Seeger RC. Phase I study of chimeric human/murine anti-ganglioside G(D2) 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. 2000 Dec 15;18(24):4077–4085. [PMID: 11118469] [PubMed]
70. Gilman AL, Ozkaynak MF, Matthay KK, Krailo M, Yu AL, Gan J, Sternberg A, Hank JA, Seeger R, Reaman GH, Sondel PM. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol. 2009 Jan 1;27(1):85. Epub 2008 Dec 1. [PMID: 19047298] [PMC free article] [PubMed]
71. Xia Y, Vetvicka V, Yan J, Hanikýrová M, Mayadas T, Ross GD. The beta-glucan-binding lectin site of mouse CR3 (CD11b/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells. J Immunol. 1999 Feb 15;162(4):2281–2290. [PMID: 9973505] [PubMed]
72. Vetvicka V, Thornton BP, Wieman TJ, Ross GD. Targeting of natural killer cells to mammary carcinoma via naturally occurring tumor cell-bound iC3b and beta-glucan-primed CR3 (CD11b/CD18) J Immunol. 1997 Jul 15;159(2):599–605. [PMID: 9218574] [PubMed]
73. Di Renzo L, Yefenof E, Klein E. The function of human NK cells is enhanced by beta-glucan, a ligand of CR3 (CD11b/CD18) Eur J Immunol. 1991 Jul;21(7):1755–1758. [PMID: 2060581] [PubMed]
74. Vetvicka V, Thornton BP, Ross GD. Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J Clin Invest. 1996 Jul 1;98(1):50–61. [PMID: 8690804] [PMC free article] [PubMed]
75. Czop JK, Austen KF. Properties of glycans that activate the human alternative complement pathway and interact with the human monocyte beta-glucan receptor. J Immunol. 1985 Nov;135(5):3388–3393. [PMID: 4045195] [PubMed]
76. Thornton BP, Vĕtvicka V, Pitman M, Goldman RC, Ross GD. Analysis of the sugar specificity and molecular location of the beta-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18) J Immunol. 1996 Feb 1;156(3):1235–1246. [PMID: 8558003] [PubMed]
77. Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostroff GR, Xing PX, Cheung NK, Ross GD. Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J Immunol. 2004 Jul 15;173(2):797–806. [PMID: 15240666] [PubMed]
78. Modak S, Cheung NK. Antibody-based targeted radiation to pediatric tumors. J Nucl Med. 2005 Jan;46 Suppl 1:157S–163S. [PMID: 15653664] [PubMed]
79. Cheung NK, Kushner BH, LaQuaglia M, Kramer K, Gollamudi S, Heller G, Gerald W, Yeh S, Finn R, Larson SM, Wuest D, Byrnes M, Dantis E, Mora J, Cheung IY, Rosenfield N, Abramson S, O'Reilly RJ. N7: a novel multi-modality therapy of high risk neuroblastoma (NB) in children diagnosed over 1 year of age. Med Pediatr Oncol. 2001 Jan;36(1):227–230. [PMID: 11464891] [PubMed]
80. Johnson E, Dean SM, Sondel PM. Antibody-based immunotherapy in high-risk neuroblastoma. Expert Rev Mol Med. 2007 Dec 17;9(34):1–21. [PMID: 18081947] [PubMed]
81. Gillies SD, Young D, Lo KM, Roberts S. Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins. Bioconjug Chem. 1993 May–Jun;4(3):230–235. [PMID: 8324014] [PubMed]
82. Gillies SD, Reilly EB, Lo KM, Reisfeld RA. Antibody-targeted interleukin 2 stimulates T-cell killing of autologous tumor cells. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1428–1432. [PMID: 1741398] [PubMed]
83. Sondel PM, Hank JA, Albertini MR, Gillies SD. Novel strategies for cytokine administration via targetting. In: Caligiuri MA, Lotze MT, editors. Cancer Drug Discovery and Development, Cytokines in the Genesis and Treatment of Cancer. Totowa, NJ: Humana Press Inc; 2008.
84. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003 Nov 1;21(21):3940–3947. Epub 2003 Sep 15. [PMID: 12975461] [PubMed]
85. Voss SD, Robb RJ, Weil-Hillman G, Hank JA, Sugamura K, Tsudo M, Sondel PM. Increased expression of the interleukin 2 (IL-2) receptor beta chain (p70) on CD56+ natural killer cells after in vivo IL-2 therapy: p70 expression does not alone predict the level of intermediate affinity IL-2 binding. J Exp Med. 1990 Oct 1;172(4):1101–1114. [PMID: 1698909] [PMC free article] [PubMed]
86. Sondel PM, Kohler PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B. Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Cancer Res. 1988 May 1;48(9):2561–2567. [PMID: 3258545] [PubMed]
87. Weil-Hillman G, Fisch P, Prieve AF, Sosman JA, Hank JA, Sondel PM. Lymphokine-activated killer activity induced by in vivo interleukin 2 therapy: predominant role for lymphocytes with increased expression of CD2 and leu19 antigens but negative expression of CD16 antigens. Cancer Res. 1989 Jul 1;49(13):3680–3688. [PMID: 2471587] [PubMed]
88. Hank JA, Surfus JE, Gan J, Jaeger P, Gillies SD, Reisfeld RA, Sondel PM. Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2 interleukin-2 fusion protein (ch14.18-IL2) Clin Cancer Res. 1996 Dec;2(12):1951–1959. [PMID: 9816154] [PubMed]
89. Kendra K, Gan J, Ricci M, Surfus J, Shaker A, Super M, Frost JD, Rakhmilevich A, Hank JA, Gillies SD, Sondel PM. Pharmacokinetics and stability of the ch14.18-interleukin-2 fusion protein in mice. Cancer Immunol Immunother. 1999 Aug;48(5):219–229. [PMID: 10478638] [PubMed]
90. Osenga KL, Hank JA, Albertini MR, Gan J, Sternberg AG, Eickhoff J, Seeger RC, Matthay KK, Reynolds CP, Twist C, Krailo M, Adamson PC, Reisfeld RA, Gillies SD, Sondel PM. Children's Oncology Group. A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group. Clin Cancer Res. 2006 Mar 15;12(6):1750–1759. [PMID: 16551859] [PMC free article] [PubMed]
91. Shusterman S, London, Gilles S, Hank JA, Voss S, Seeger RC, Hecht T, Reisfeld R, Maris JM, Sondel PM. Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children's Oncology Group (COG) phase II study. J. Clin. Oncol. 2008;26(15s):132s. (abstract 3002)
92. Shusterman S, London WB, Gillies SD, Hank JA, Voss S, Seeger RC, Reynolds CP, Kimball J, Albertini MA, Wagner B, Gan J, Eickhoff J, DeSantes KD, Cohn SL, Hecht T, Gadbaw B, Reisfeld RA, Maris JM, Sondel PM, et al. Anti-tumor activity of hu14.18-IL2 in relapsed/refractory neuroblastoma patients: a Children’s Oncology Group (COG) phase II study. 2010 To be Submitted. [PMC free article] [PubMed]
93. Wang X, Luo W, Foon KA, Ferrone S. Tumor associated antigen (TAA) mimicry and immunotherapy of malignant diseases from anti-idiotypic antibodies to peptide mimics. Cancer Chemother Biol Response Modif. 2001;19:309–326. [PMID: 11686020] [PubMed]
94. Cheung NK, Guo HF, Heller G, Cheung IY. Induction of Ab3 and Ab3' antibody was associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma. Clin Cancer Res. 2000 Jul;6(7):2653–2660. [PMID: 10914706] [PubMed]
95. Chatterjee MB, Foon KA, Köhler H. Idiotypic antibody immunotherapy of cancer. Cancer Immunol Immunother. 1994 Feb;38(2):75–82. Review. [PMID: 8306369] [PubMed]
96. Chatterjee M, Mrozek E, Vaickus L, Oseroff A, Stoll H, Russell D, Kohler H, Foon KA. Antiidiotype (Ab2) vaccine therapy for cutaneous T-cell lymphoma. Ann N Y Acad Sci. 1993 Aug 12;690:376–377. [PMID: 8368761] [PubMed]
97. Chatterjee M, Barcos M, Han T, Liu XL, Bernstein Z, Foon KA. Shared idiotype expression by chronic lymphocytic leukemia and B-cell lymphoma. Blood. 1990 Nov 1;76(9):1825–1829. [PMID: 2224130] [PubMed]
98. Luo W, Ko E, Hsu JC, Wang X, Ferrone S. Targeting melanoma cells with human high molecular weight-melanoma associated antigen-specific antibodies elicited by a peptide mimotope: functional effects. J Immunol. 2006 May 15;176(10):6046–6054. [PMID: 16670313] [PubMed]
99. Fest S, Huebener N, Weixler S, Bleeke M, Zeng Y, Strandsby A, Volkmer-Engert R, Landgraf C, Gaedicke G, Riemer AB, Michalsky E, Jaeger IS, Preissner R, Förster-Wald E, Jensen-Jarolim E, Lode HN. Characterization of GD2 peptide mimotope DNA vaccines effective against spontaneous neuroblastoma metastases. Cancer Res. 2006 Nov 1;66(21):10567–10575. [PMID: 17079481] [PubMed]
100. Coughlin CM, Vance BA, Grupp SA, Vonderheide RH. RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy. Blood. 2004 Mar 15;103(6):2046–2054. Epub 2003 Nov 20. [PMID: 14630810] [PubMed]
101. Rossig C, Brenner MK. Genetic modification of T lymphocytes for adoptive immunotherapy. Mol Ther. 2004 Jul;10(1):5–18. [PMID: 15233937] [PubMed]
102. Rossig C, Bollard CM, Nuchtern JG, Merchant DA, Brenner MK. Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes. Int J Cancer. 2001 Oct 15;94(2):228–236. [PMID: 11668503] [PubMed]
103. Gonzalez S, Naranjo A, Serrano LM, Chang WC, Wright CL, Jensen MC. Genetic engineering of cytolytic T lymphocytes for adoptive T-cell therapy of neuroblastoma. J Gene Med. 2004 Jun;6(6):704–711. [PMID: 15170741] [PubMed]
104. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther. 2007 Apr;15(4):825–833. Epub 2007 Feb 13. [PMID: 17299405] [PubMed]
105. Jensen MC, Clarke P, Tan G, Wright C, Chung-Chang W, Clark TN, Zhang F, Slovak ML, Wu AM, Forman SJ, Raubitschek A. Human T lymphocyte genetic modification with naked DNA. Mol Ther. 2000 Jan;1(1):49–55. [PMID: 10933911] [PubMed]
106. Serrano LM, Pfeiffer T, Olivares S, Numbenjapon T, Bennitt J, Kim D, Smith D, McNamara G, Al-Kadhimi Z, Rosenthal J, Forman SJ, Jensen MC, Cooper LJ. Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood. 2006 Apr 1;107(7):2643–2652. Epub 2005 Dec 13. [PMID: 16352804] [PubMed]
107. Cooper LJ, Ausubel L, Gutierrez M, Stephan S, Shakeley R, Olivares S, Serrano LM, Burton L, Jensen MC, Forman SJ, DiGiusto DL. Manufacturing of gene-modified cytotoxic T lymphocytes for autologous cellular therapy for lymphoma. Cytotherapy. 2006;8(2):105–117. [PMID: 16698684] [PubMed]
108. Savoldo B, Rooney CM, Di Stasi A, Abken H, Hombach A, Foster AE, Zhang L, Heslop HE, Brenner MK, Dotti G. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood. 2007 Oct 1;110(7):2620–2630. Epub 2007 May 16. [PMID: 17507664] [PubMed]