a Antibodies were injected intravenously unless otherwise stated.IT = intrathecal b BM CR was proportion of patients clearing marrow disease.Overall response = CR + PR, unless otherwise stated c 1 radiographic and 2 CSF cytologic responses from the first 12 patients d I=phase I, II=phase II

e No.of responses/no.of evaluable patients with neuroblastoma f Patients without HAMA after 400 mg/m2 (4 cycles of 10 days/cycle, 10 mg/m2 day) were treated ql-2 months (100 mg/m2/

cycle) until 24 months from the first day of enrollment on the protocol g Only patients with evaluable disease (primary resistance to induction or secondary resistance to retrieval therapy) were included in this analysis lating GD2 in most patients has not interfered with antibody targeting which typically achieved high percent injected dose per gram (%ID/g) with high tumor-to-normal-tissue ratio, and unusually low liver and spleen uptake in patient studies (Yeh et al. 1991; Larson et al. 2000).

Clinical Trials

The first IgG anti-GD2 MAb to undergo clinical testing was 3F8 (murine IgG3; Table 14.3; Cheung et al. 1987, 1998a), followed subsequently by 14.G2a (murine IgG2a; Handgretinger et al. 1992; Frost et al. 1997). and a chimeric form ch14.18 (Yu et al. 1998). In clinical trials (Yu et al. 1998; Handgretinger et al. 1995; Ozkaynak et al. 2000), ch14.18 had a more prolonged serum half-life and lower immunogenicity compared with its mouse counterpart. Most of the responses noted in phase I and II clinical trials of unconjugated anti-GD2 MAbs involved metastatic disease in bone marrow, with less certain effects on bulky tumors. The predominant toxicity was pain, attributed to cross-reactivity of antibodies with peripheral pain fibers (Lammie et al. 1993; Xiao et al. 1997; Yuki et al. 1997). Other side effects included tachycardia, hypotension, fever, anaphylactoid reactions, nausea, vomiting, diarrhea, and transient neuropathy. Most side effects were dose dependent, rarely noted at dosages of <10mg/m2 (14G.2a or ch14.18) or <1mg/m2 (3F8), and compatible with outpatient treatment. Over a 15-year period, more than 350 patients with NB have been treated with >10,000 infusions of 3F8 at Memorial Sloan-Ketter-ing Cancer Center. There was no treatment-associated mortality. Similarly, the COG (and its component organizations) have been administering 14.G2a or ch14.18 anti-GD2 MAb since 1989 with good safety record. Patients have been followed for up to 15 years. No long-term neurological complications have been noted. The clinical development of anti-GD2 MAb was partly hindered by its pain side effects which have precluded dose escalation.

Although the anti-tumor effect of anti-GD2 MAb was modest,response of microscopic marrow disease was more consistent (Cheung et al. 1998b, 2001a, 2003a,b; Kushner et al. 2001). An association of human anti-mouse antibody (HAMA) response and favorable patient outcome, plus the induction of anti-idiotypic Ab2 and anti-idiotypic Ab3/antibodies through the idiotype network, implicate the potential role of the host immune response in maintaining clinical remission (Cheung et al. 1994, 2000). In a recent update of 98 patients with stage-4 NB newly diagnosed after 18 month of age, who received anti-GD2 MAb 3F8 as part of their combined modality therapy at MSKCC, the induction of a HAMA response and a lower number of tumor cells in the diagnostic bone marrow were the most significant independent prognostic variables for both progression-free and overall survival (N.-K.V. Cheung et al., unpublished results).

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