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-FcγR 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 FcγR 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 = 0.03). There was a trend toward patients with the FcγR2A 131-H/H genotype showing a higher response rate than other FcγR2A genotypes (P = 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.

• Authors: David C Delgado, Jacquelyn A Hank, Jill Kolesar, David Lorentzen, Jacek Gan, Songwon Seo, Kyungmann Kim, Suzanne Shusterman, Stephen D Gillies, Ralph A Reisfeld, Richard Yang, Brian Gadbaw, Kenneth B DeSantes, Wendy B London, Robert C Seeger, John M Maris, Paul M Sondel
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 23 Pg. 9554-61 (Dec 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20935224 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• FCGR3A protein, human
• Fc gamma receptor IIA
• HLA Antigens
• HLA-B Antigens
• HLA-C Antigens
• Interleukin-2
• Ligands
• Receptors, IgG
• Receptors, KIR
• lorukafusp alfa

Topics

• Adolescent
• Antibodies, Monoclonal (therapeutic use)
• Child
• Child, Preschool
• Genotype
• HLA Antigens (genetics)
• HLA-B Antigens (genetics)
• HLA-C Antigens (genetics)
• Humans
• Infant
• Interleukin-2 (therapeutic use)
• Killer Cells, Natural (metabolism)
• Ligands
• Neuroblastoma (drug therapy, genetics)
• Polymorphism, Genetic
• Receptors, IgG (genetics)
• Receptors, KIR (genetics)
• Treatment Outcome
• Young Adult