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

Abstract

PurposeThe 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.Patients and MethodsHu14.18-IL2 was given intravenously (12 mg/m2/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 [123I]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.ResultsThirty-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.ConclusionPatients 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.

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2immunotherapy and isotretinoin: a prospective Phase II study

“…Achieving a minimal disease state (CR/ VGPR) after relapse remains a challenge but may be facilitated through close monitoring of disease status: asymptomatic, limited relapse may be more amenable to control than symptomatic, widespread, and bulky relapsed disease. 44 Greater anti-NB activity is a possibility with new generations of antibody-based immunotherapy 26,45,46 and other targeted therapies. 40 47 Major organ toxicity had to be grade 2 by Common Terminology Criteria for Adverse Events Version 2.0 (CTCAEv2.0), although neutrophil count 500/ml and platelet count 10,000/ml were acceptable.…”

“…Immunosuppressive chemotherapy prevented early emergence of human anti-mouse antibody (HAMA). 24 As with other anti-G D2 mAbs, 25,26 activity was noted against NB in bone marrow (BM), but not against soft tissue tumor or progressive disease (PD). The ability to mount a HAMA response was consistently correlated with long-term survival, possibly related to the anti-idiotype network or induction of a host antitumor response.…”

Overview and recent advances in the treatment of neuroblastoma

“…These results led to a current COG study combining ch14.18 (dinutuximab) with irinotecan and temozolomide (NCT01767194). In a separate study of the Hu14.18-IL-2 immunocytokine, there were no responses observed in 13 patients with measurable soft tissue neuroblastoma tumors, whereas in those with only MIBG-avid or bone marrow disease, there were 5 complete responses out of 23 patients [141]. Further analyses have revealed that mismatches for natural killer (NK) cell KIR/KIRligand genotypes and polymorphisms in the Fcγ receptor have also been associated with better responses to anti-GD2 immunotherapy [142,143].…”

Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution

“…Treatment with IL-2 immunocytokines has proven to be superior to treatment with equivalent antibody and cytokine given as separate agents (4)(5)(6)(7). Nonetheless, systemic dose-limiting side effects have been observed after IL-2 immunocytokine administration, despite its expected tumor localization (8,9).…”