Interleukin-15 Enhances Anti-GD2 Antibody-Mediated Cytotoxicity in an Orthotopic PDX Model of Neuroblastoma

• Published in: Clinical cancer research 2019-12, Vol.25 (24), p.7554-7564
• Main Authors: Nguyen, Rosa, Moustaki, Ardiana, Norrie, Jacqueline L, Brown, Shantel, Akers, Walter J, Shirinifard, Abbas, Dyer, Michael A
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antibody-Dependent Cell Cytotoxicity - immunology; Child; Female; Gangliosides - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Humans; Immunotherapy - methods; Interleukin-15 - immunology; Interleukin-2 - immunology; Killer Cells, Natural - immunology; Neuroblastoma - immunology; Neuroblastoma - pathology; Neuroblastoma - therapy; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1045

Immunotherapy with IL2, GM-CSF, and an anti-disialoganglioside (GD2) antibody significantly increases event-free survival in children with high-risk neuroblastoma. However, therapy failure in one third of these patients and IL2-related toxicities pose a major challenge. We compared the immunoadjuvant effects of IL15 with those of IL2 for enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) in neuroblastoma. We tested ADCC against neuroblastoma patient-derived xenografts (PDX) and and examined the functional and migratory properties of NK cells activated with IL2 and IL15. In cell culture, IL15-activated NK cells induced higher ADCC against two GD neuroblastoma PDXs than did IL2-activated NK cells ( < 0.001). This effect was dose-dependent ( < 0.001) and was maintained across several effector-to-tumor ratios. As compared with IL2, IL15 also improved chemotaxis of NK cells, leading to higher numbers of tumorsphere-infiltrating NK cells ( = 0.002). In an orthotopic PDX model, animals receiving chemoimmunotherapy with an anti-GD2 antibody, GM-CSF, and a soluble IL15/IL15Rα complex had greater tumor regression than did those receiving chemotherapy alone ( = 0.012) or combined with anti-GD2 antibody and GM-CSF with ( = 0.016) or without IL2 ( = 0.035). This was most likely due to lower numbers of immature tumor-infiltrating NK cells (DX5 CD27 ) after IL15/IL15Rα administration ( = 0.029) and transcriptional upregulation of . The substitution of IL15 for IL2 leads to significant tumor regression and and supports clinical testing of IL15 for immunotherapy in pediatric neuroblastoma.