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.

Download full-text


Available from: Richard Yang,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: Natural killer (NK) cells efficiently cytolyse tumors and virally infected cells. Despite the important role that interleukin (IL)-2 plays in stimulating the proliferation of NK cells and increasing NK cell activity, little is known about the alterations in the global NK cell proteome following IL-2 activation. To compare the proteomes of naïve and IL-2-activated primary NK cells and identify key cellular pathways involved in IL-2 signaling, we isolated proteins from naïve and IL-2-activated NK cells from healthy donors, the proteins were trypsinized and the resulting peptides were analyzed by 2D LC ESI-MS/MS followed by label-free quantification. In total, more than 2000 proteins were identified from naïve and IL-2-activated NK cells where 383 proteins were found to be differentially expressed following IL-2 activation. Functional annotation of IL-2 regulated proteins revealed potential targets for future investigation of IL-2 signaling in human primary NK cells. A pathway analysis was performed and revealed several pathways that were not previously known to be involved in IL-2 response, including ubiquitin proteasome pathway, integrin signaling pathway, platelet derived growth factor (PDGF) signaling pathway, epidermal growth factor receptor (EGFR) signaling pathway and Wnt signaling pathway. Biological significance: The development and functional activity of natural killer (NK) cells is regulated by interleukin (IL)-2 which stimulates the proliferation of NK cells and increases NK cell activity. With the development of IL-2-based immunotherapeutic strategies that rely on the IL-2-mediated activation of NK cells to target human cancers, it is important to understand the global molecular events triggered by IL-2 in human NK cells. The differentially expressed proteins in human primary NK cells following IL-2 activation identified in this study confirmed the activation of JAK-STAT signaling pathway and cell proliferation by IL-2 as expected, but also led to the discovery and identification of other factors that are potentially important in IL-2 signaling. These new factors warrant further investigation on their potential roles in modulating NK cell biology. The results from this study suggest that the activation of NK cells by IL-2 is a dynamic process through which proteins with various functions are regulated. Such findings will be important for the elucidation of molecular pathways involved in IL-2 signaling in NK cells and provide new targets for future studies in NK cell biology.
    Journal of proteomics 06/2013; 91. DOI:10.1016/j.jprot.2013.06.024 · 3.89 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.
    Frontiers in Immunology 03/2013; 4:76. DOI:10.3389/fimmu.2013.00076
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Disease recurrence is frequent in high-risk neuroblastoma (NBL) patients even after multi-modality aggressive treatment [a combination of chemotherapy, surgical resection, local radiation therapy, autologous stem cell transplantation, and cis-retinoic acid (CRA)]. Recent clinical studies have explored the use of monoclonal antibodies (mAbs) that bind to disialoganglioside (GD(2)), highly expressed in NBL, as a means to enable immune effector cells to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical data indicate that ADCC can be more effective when appropriate effector cells are activated by cytokines. Clinical studies have pursued this by administering anti-GD(2) mAb in combination with ADCC-enhancing cytokines (IL2 and GM-CSF), a regimen that has demonstrated improved cancer-free survival. More recently, early clinical studies have used a fusion protein that consists of the anti-GD(2) mAb directly linked to IL2, and anti-tumor responses were seen in the Phase II setting. Analyses of genes that code for receptors that influence ADCC activity and natural killer (NK) cell function [Fc receptor (FcR), killer immunoglublin-like receptor (KIR), and KIR-ligand (KIR-L)] suggest patients with anti-tumor activity are more likely to have certain genotype profiles. Further analyses will need to be conducted to determine whether these genotypes can be used as predictive markers for favorable therapeutic outcome. In this review, we discuss factors that affect response to mAb-based tumor therapies such as hu14.18-IL2. Many of our observations have been made in the context of NBL; however, we will also include some observations made with mAbs targeting other tumor types that are consistent with results in NBL. Therefore, we hypothesize that the NBL observations discussed here may also be relevant to mAb therapy for other cancers, in which ADCC is known to play a role.
    Frontiers in Pharmacology 05/2012; 3:91. DOI:10.3389/fphar.2012.00091 · 3.80 Impact Factor
Show more