TY - JOUR
T1 - Interleukin-15 enhances anti-GD2 antibody-mediated cytotoxicity in an orthotopic PDX model of neuroblastoma
AU - Nguyen, Rosa
AU - Moustaki, Ardiana
AU - Norrie, Jacqueline L.
AU - Brown, Shantel
AU - Akers, Walter J.
AU - Shirinifard, Abbas
AU - Dyer, Michael A.
N1 - Funding Information:
We thank Asa Karlstrom, PhD, for regulatory support; Nisha Badders, PhD, ELS, for editing the manuscript; Jennifer Peters, PhD, for optimizing the live-cell microscopy protocol; Melissa Johnson, BS, for performing tumor injections; Benjamin Youngblood, PhD, for comments and suggestions; Merck Serono and Children's GMP, LLC for providing hu14.18K322A for our studies; and the NCI Biological ResourceBranchforproviding IL2 and IL15.Thiswork wassupported by the NIH grant P30 CA021765 and ALSAC (all authors); ASCO Conquer Cancer Young Investigator Award (12822; to R. Nguyen); R50CA211481 (to W.J. Akers); and EY014867, EY018599, and CA168875 (to M.A. Dyer). This research was supported by Howard Hughes Medical Institute.
Funding Information:
We thank Asa Karlstrom, PhD, for regulatory support; Nisha Badders, PhD, ELS, for editing the manuscript; Jennifer Peters, PhD, for optimizing the live-cell microscopy protocol; Melissa Johnson, BS, for performing tumor injections; Benjamin Youngblood, PhD, for comments and suggestions; Merck Serono and Children's GMP, LLC for providing hu14.18K322A for our studies; and the NCI Biological Resource Branch for providing IL2 and IL15. This work was supported by the NIH grant P30 CA021765 and ALSAC (all authors); ASCO Conquer Cancer Young Investigator Award (12822; to R. Nguyen); R50CA211481 (to W.J. Akers); and EY014867, EY018599, and CA168875 (to M.A. Dyer). This research was supported by Howard Hughes Medical Institute.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-1045
DO - 10.1158/1078-0432.CCR-19-1045
M3 - Article
C2 - 31455682
AN - SCOPUS:85076502997
SN - 1078-0432
VL - 25
SP - 7554
EP - 7564
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -