Abstract CT410: Immune activation, clinical response and survival following long-term infusion of anti-GD2 antibody ch14.18/CHO in combination with interleukin-2 in high-risk neuroblastoma patients
Authors: Lode Holger , Jensen Christian , Siebert Nikolai , Kietz Silke , Ehlert Karoline , Müller Ina , Ladenstein Ruth , Janzek Evelyne , Loibner Hans 
Published: May 2015

Abstract
Purpose: Immunotherapy with monoclonal anti-GD2 antibody (mAb) ch14.18 in combination with cytokines effectively prolonged survival in high risk neuroblastoma (NB). We piloted a less toxic treatment using continuous infusion of ch14.18/CHO in combination with subcutaneous interleukin-2 (IL-2) and report initial clinical response and survival.
Methods and Materials: 53 high risk NB patients received up to 6 cycles of 6x106 IU/m2 s.c. IL-2 (d1-5; 8-12), continuous infusion of 100 mg/m2 ch14.18/CHO (d8-17) and 160 mg/m2 oral 13-cis-RA (d19-32) in a single center compassionate use program. Killer immunoglobulin-like receptor (KIR)/KIR-ligand (KIRL) mismatch and Fcγ-receptor (FCGR) was analyzed with a validated PCR-based analysis of KIR, HLA, FCGR2A (H131R), -3A (V158F) and -3B (NA1/NA2) polymorphisms. Antibody levels and GD2 specific killing of neurpblastoma cells by ADCC, CDC, and whole blood were sequentially analyzed. Clinical response was assessed by mIBG, MRI/CT, bone marrow- and catecholamine- analysis before, after 2/3 and after 5/6 cycles of immunotherapy in patients with measurable disease.
Results: : In the patients receiving ch14.18/CHO continuous infusions significantly less i.v. morphine was used compared to patients who receive ch14.18/CHO bolus infusions. In many patients it was possible to discontinue i.v. morphine and to treat pain with oral Gabapentin only. Response rates were 41.7 % in mIBG (15/36), 31.8 % MRI/CT (7/22), 28.6 % bone marrow- (6/21) and 38.1 % in catecholamine- (8/21) measurements. External review of mIBG responses of 28 patients confirmed a 32.1% response rate (9/28). The overall response following INRG guide lines was determined at 30% (12/40). The event-free-survival rate in the entire cohort was 32.4 % (observation 3.2 years, mean: 1.6 years) and an overall-survival rate of 66.8% (observation 3.9 years, mean: 3.1 years). Patients with KIR/KIRL mismatch and high affinity FCGR alleles showed a trend towards longer event-free survival (P = 0.08), which supports NK cell mediated antibody dependent cytotoxicity as the mechanism of action. Determination of antibody levels and functional immune parameters (ADCC, CDC and WBT) indicate persistent anti-neuroblastoma immune-activity measurable before susequent treatment cycles.
Conclusion: Continuous infusion of anti-GD2 Ab ch14.18/CHO reduces the pain side effect, shows clinical activity in NB patients and improves the outcome. Analysis of KIR/KIRL-mismatch and FCGR-polymorphisms by genotyping may predict clinical outcome in patients receiving ch14.18/CHO. Functional immune parameters indicate anti-neuroblastoma activity over the entire treatment period. These results are subject to prospective confirmation in a SIOPEN Phase II study (EudraCT: 2009-018077-31).
Citation Format: Holger Lode, Christian Jensen, Nikolai Siebert, Silke Kietz, Karoline Ehlert, Ina Müller, Ruth Ladenstein, Evelyne Janzek, Hans Loibner. Immune activation, clinical response and survival following long-term infusion of anti-GD2 antibody ch14.18/CHO in combination with interleukin-2 in high-risk neuroblastoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT410. doi:10.1158/1538-7445.AM2014-CT410