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

Abstract

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) <i>in vitro</i> and <i>in vivo</i> 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 (<i>P</i> < 0.001). This effect was dose-dependent (<i>P</i> < 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 <i>in vitro</i> (<i>P</i> = 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 (<i>P</i> = 0.012) or combined with anti-GD2 antibody and GM-CSF with (<i>P</i> = 0.016) or without IL2 (<i>P</i> = 0.035). This was most likely due to lower numbers of immature tumor-infiltrating NK cells (DX5⁺CD27⁺) after IL15/IL15Rα administration (<i>P</i> = 0.029) and transcriptional upregulation of <i>Gzmd</i>. The substitution of IL15 for IL2 leads to significant tumor regression <i>in vitro</i> and <i>in vivo</i> and supports clinical testing of IL15 for immunotherapy in pediatric neuroblastoma.