Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children's Oncology Group (COG) Phase II Study

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 10/2010; 28(33):4969-75. DOI: 10.1200/JCO.2009.27.8861
Source: PubMed


The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma.
Hu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks.
Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results.
Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.

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    • "Surprisingly, statistical analysis showed a positive correlation between sEPCR and CD3, CD8 and a negative correlation between CD56 (NK cells), CD29 (integrin β-1, present on all blood cells), CD294 (TH2 cells), and the immune cells containing IL-2, IL-17a, IL-10 and IL-21. IL-2 is one of a multitude of cytokines produced by lymphocytes and monocytes that trigger a cascade of immune reactions ( 33 ) . IL-10 inhibits the synthesis of pro-inflammatory cytokines such as IFN-γ, IL-2 and TNFα. "
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    • "Recently, immunotherapy was found to increase overall survival when combined with maintenance therapy (Yu et al, 2010) and has now become part of the standard of care, despite proving ineffective in patients with recurrent or refractory bulky disease (Shusterman et al, 2010). Moreover, these therapeutic options are all extremely aggressive and toxic (Ishola and Chung, 2007; Shusterman et al, 2010; Yu et al, 2010), suggesting that the limit of therapy intensification may have been reached. Safer and more efficacious therapeutic options are urgently needed, thus warranting the evaluation of innovative therapeutic strategies in clinically relevant models of high-risk neuroblastoma. "
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    • "Due to yet small patient cohorts, the role of FcγRIIIa-F158V polymorphism in treatment with GD2 antibodies has not been studied up to now. However, there are a variety of further studies ongoing which investigate the in vivo efficacy of GD2 antibodies (Navid et al., 2010; Shusterman et al., 2010; Yu et al., 2010; Alderson and Sondel, 2011; Simon et al., 2011). Yu et al. demonstrated in a randomized trial a significantly better event-free survival for patients who received a combination of ch14.18, "
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    Frontiers in Immunology 03/2013; 4:76. DOI:10.3389/fimmu.2013.00076
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