Genotypes of NK Cell KIR Receptors, Their Ligands, and Fcγ Receptors in the Response of Neuroblastoma Patients to Hu14.18-IL2 Immunotherapy

Abstract

Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-FcgR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific FcgR alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P ¼ 0.03). There was a trend toward patients with the FcgR2A 131-H/H genotype showing a higher response rate than other FcgR2A genotypes (P ¼ 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response. Cancer Res; 70(23); 9554-61. Ó2010 AACR.

KIR/HLA Interactions Negatively Affect Rituximab- but Not GA101 (Obinutuzumab)-Induced Antibody-Dependent Cellular Cytotoxicity

“…The FCGR3A V158F polymorphism, previously identified as a predictor of clinical responses to mAb treatment, showed only a minor influence by guest on May 11, 2018 http://www.jimmunol.org/ on rituximab-induced NK cell activation in our experiments and was significantly weaker than the effect of KIR ligand status. Again, these data are in agreement with clinical data from a small cohort of neuroblastoma patients receiving treatment with an IL-2-coupled Ab, where KIR ligand status but not the FCGR3A genotype was associated with response to treatment (26).…”

“…Interestingly, in patients with neuroblastoma, presence of KIR ligands was also shown to associate with progression-free survival after Ab treatment, with patients carrying all KIR ligands (and therefore having no KIR + unlicensed NK cells) responding poorly to Ab treatment (25,26). No clinical studies have so far evaluated the role of KIR/HLA interactions in patients treated with CD20 Abs.…”

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

“…Furthermore, clinical studies with the murine anti-GD 2 Ab 3F8 or humanized immunocytokine hu14.18-IL-2 demonstrated superior clinical outcome in patients missing inhibitory KIRL. [17][18][19] Similar observations were made in lymphoma patients treated with rituximab. 20 Extending on these results, interactions of activating KIR/KIRL has been recently studied in a number of malignancies.…”

“…8 In treatment of NB with the murine anti-GD 2 Ab 3F8 or humanized immunocytokine hu14.18-IL-2, mismatch of inhibitory KIRL was associated with improved clinical outcome. [17][18][19] These observations were also made in lymphoma patients treated with rituximab suggesting KIR/ KIRL-dependent effects in NK-mediated tumor cell lysis. 20 Surprisingly, in the present study we did not find significant differences in ADCC and EFS between matched and mismatched inhibitory KIR/KIRL genotypes in our patient cohort (data not shown), indicating only a minor role for exclusive consideration of the 2DL3/HLA-C1 and 3DL1/HLA-Bw4 KIR/KIRL repertoire.…”

Overview and recent advances in the treatment of neuroblastoma

“…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]. With the significant side effects and known limitations of anti-GD2 antibody immunotherapy, many other immunologic approaches have been evaluated recently, including therapy with immunomodulatory CTLA4 checkpoint inhibitors [144], antitumor vaccines [145,146], and cell-based immunotherapy using either NK cells [147] or anti-GD2 targeted autologous T cells [148], which have been shown to have antitumor activity, including activity in cases with measurable disease [149,150].…”