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

Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, USA.
Cancer Research (Impact Factor: 9.33). 10/2010; 70(23):9554-61. DOI: 10.1158/0008-5472.CAN-10-2211
Source: PubMed


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.

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Available from: Richard Yang
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    • "Some IL-2 centered strategies have already been approved by the FDA for the treatment of metastatic melanoma [16] and renal cell carcinoma [17]. Intense research (basic, translational, and clinical) is also underway on the use of IL-2 and IL-2-antibody conjugates (immunocytokines) to boost the anti-cancer activities of NK [18] [19] [20] [21]. Our initial studies on the characterization of the global proteome of naïve and IL-2-stimulated human NK cells reveal a large number of proteins exhibiting changes in expression levels upon IL-2 stimulation. "
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    • "In adult acute myeloid leukemia (AML) and pediatric acute lymphoblastic leukemia (ALL) donor versus recipient NK cell alloreactivity is a key mechanism after HLA mismatched, haploidentical SCT, and has been reviewed elsewhere (Velardi et al., 2012). These “unlicensed” NK cells are characterized in the autologous setting by lacking self-KIRs and are thought to be beneficial in patients with neuroblastoma as well (Venstrom et al., 2009; Delgado et al., 2010). Interestingly, a recent study investigating the differential potential for ADCC of “licensed” and “unlicensed” NK cells in neuroblastoma, showed that “unlicensed” NK cells mediate ADCC most effectively against neuroblastoma cell lines under inflammatory conditions (Tarek et al., 2012). "
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    • "To test these hypotheses our lab analyzed the relationship between FcR genotype and KIR/KIR-L match or mismatch status with regard to the clinical response of patients following hu14.18-IL2 IC therapy using patient samples from the phase II COG NBL study (Delgado et al., 2010). We performed FcR and KIR/KIR-L genotyping on DNA isolated from clinical samples from patients enrolled in this study (n = 38). "
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