Survival of neuroblastoma patients treated by long-term infusion of anti-GD2 antibody ch14.18/CHO and killer-cell Ig-like receptor (KIR) genotypes and Fcγ-receptor polymorphisms.

Abstract

111 Background: Receptors expressed on natural killer (NK) cells and their ligands on target cells involved in antibody-dependent cell-mediated cytotoxicity (ADCC) may influence outcome in patients (pts) with high-risk relapsed/refractory neuroblastoma (NB) treated by long-term infusion (LTI) of anti-GD2 antibody 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: The survival update of the APN311-303 cohort revealed 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. In this cohort, we identified 26/53 pts with the NK- stimulatory KIR haplotype (2DS2+) who had superior OS- and PFS-rates compared to 18/53 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 20/53 patients with high affinity FCGR polymorphisms (p < 0.01). 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 (23±6 % vs. 6±2%, p < 0.01). A similar effect was observed in pts with high affinity FCGR polymorphisms with an ADCC increase of 20±6% compared to 11±2% in the low affinity FCGR control. Conclusions: KIR-haplotypes and FCGR- polymorphisms correlated with the functional immune parameter ADCC and clinical outcome, and thus support the relevance of ADCC for clinical efficacy of ch14.18/CHO in neuroblastoma.