Interleukin-15 enhances anti-GD2 antibody-mediated cytotoxicity in an orthotopic PDX model of neuroblastoma

Rosa Nguyen, Ardiana Moustaki, Jacqueline L. Norrie, Shantel Brown, Walter J. Akers, Abbas Shirinifard, Michael A. Dyer

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Purpose: 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. Experimental Design: We tested ADCC against neuroblastoma patient-derived xenografts (PDX) in vitro and in vivo and examined the functional and migratory properties of NK cells activated with IL2 and IL15. Results: In cell culture, IL15-activated NK cells induced higher ADCC against two GDþ neuroblastoma PDXs than did IL2-activated NK cells (P < 0.001). This effect was dose-dependent (P < 0.001)

effector-to-tumor ratios. As compared with IL2, IL15 also improved chemotaxis of NK cells, leading to higher numbers of tumorsphere-infiltrating NK cells in vitro (P ¼ 0.002). In an orthotopic PDX model, animals receiving chemoimmunotherapy with an anti-GD2 antibody, GM-CSF, and a soluble IL15/IL15Ra complex had greater tumor regression than did those receiving chemotherapy alone (P ¼ 0.012) or combined with anti-GD2 antibody and GM-CSF with (P ¼ 0.016) or without IL2 (P ¼ 0.035). This was most likely due to lower numbers of immature tumor-infiltrating NK cells (DX5þCD27þ) after IL15/IL15Ra administration (P ¼ 0.029) and transcriptional upregulation of Gzmd. Conclusions: The substitution of IL15 for IL2 leads to significant tumor regression in vitro and in vivo and supports clinical testing of IL15 for immunotherapy in pediatric neuroblastoma.

Original languageEnglish (US)
Pages (from-to)7554-7564
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number24
DOIs
StatePublished - Dec 15 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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