Oral Presentation Advances in Neuroblastoma Research Congress 2016

Killer-cell Ig-like receptor (KIR) haplotypes and Fcγ-receptor polymorphisms correlate with antibody-dependent cell-mediated cytotoxicity levels and survival of high-risk relapsed/refractory neuroblastoma patients treated by long-term infusion of anti-GD2 antibody ch14.18/CHO in combination with interleukin-2 (IL-2). (#125)

Holger N Lode 1 , Sascha Troschke-Meurer 1 , Domonique Valteau-Couanet 2 , Alberto Garaventa 3 , Juliet Gray 4 , Victoria Castel 5 , Isaac Yaniv 6 , Nikolai Siebert 1 , Christin Eger 1 , Madlen Jüttner 1 , Silke Kietz 1 , Karoline Ehlert 1 , Evelyne Janzek 7 , Hans Loibner 7 , Ruth Ladenstein 8
  1. University Medicine Greifswald, Greifswald, Germany
  2. Institut Gustave Roussy, Villejuif, France
  3. Gaslini Instutite, Genova, Italy
  4. University Hospital Southampton, Southampton, United Kingdom
  5. University Hospital La Fe, Valencia, Spain
  6. Schneider Children’s Medical Centre of Israel, , Petach Tikvah, Israel
  7. Apeiron Biologics, Vienna, Austria
  8. Children's Cancer Research Institute, Vienna, Austria

Background: Killer-cell Ig-like receptors expressed on natural killer (NK) cells and their ligands on target cells may predict outcome in patients (pts) with high-risk relapsed/refractory neuroblastoma (NB) treated by LTI of ch14.18/CHO.

Methods: 53 pts received 6x106 IU/m2 sc IL-2 (d1-5; 8-12), LTI of 100 mg/m2 ch14.18/CHO (d8-17) and 160 mg/m2 oral 13-cis-RA (d19-32) in a closed single center program (53 pts) (APN311-303). Polymorphisms in Fcγ-receptor genes 2A (H131R), -3A (V158F) and -3B (NA1/NA2), and KIR- as well as KIR ligand expression (HLA-C1; HLA-C2; HLA-Bw4+) were determined by real-time PCR.

Results: A best response rate of 40.5% translated into a 5-y OS of 56.4±7.1% (mean OS 4.35y [0.3-6.2y]) and a 5-y PFS of 29.1±6.3% (mean PFS 2.4y [0.1 - 5.9y]). Median TTP/PFS was 1.35 y (95% CI: 0.21-2.48 y). This result is clearly superior to historical controls not treated with ch14.18/CHO with a 5-y OS of 14.8±6.8% (p<0.005), indicating clinical efficacy of the treatment.

We identified 21/53 pts with the NK- stimulatory KIR haplotype (2DS2+) who had superior OS- and PFS-rates compared to 16/53 pts with an inhibitory haplotype and KIR/KIR-ligand match (2DS2-, 3DL1+, Bw4+) (p<0.02). Similarly, we found 33/53 pts with low affinity FCGR alleles (FCGR2A-H131R/R and/or FCGRA3A-V158 F/F). These patients showed lower PFS rates compared to 19/53 patients with high affinity FCGR polymorphisms (p<0.01).

Importantly, ADCC analysis on day 15 of cycle 1 showed higher levels in the pt group with NK- stimulatory versus NK- inhibitory KIR/KIR ligand haplotypes (27±5 % vs. 12±3%, p< 0.01). A similar effect was observed in pts with high affinity FCGR polymorphisms with an ADCC increase of 21±7% compared to 11±2% in the low affinity FCGR control.

Conclusion: KIR-haplotypes and FCGR- polymorphisms correlated with the functional immune parameter ADCC and clinical outcome, and may therefore be useful biomarkers for LTI with ch14.18/CHO.