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The IL-15 superagonist ALT-803 enhances anti-CD20 antibody-directed NK cell ADCC and in vivo clearance of B cell lymphomas

  • 1,
  • 2,
  • 2,
  • 1,
  • 2,
  • 2,
  • 2 and
  • 1
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P168

https://doi.org/10.1186/2051-1426-2-S3-P168

Published: 6 November 2014

Keywords

  • Cell Lymphoma
  • Follicular Lymphoma
  • Daudi Cell
  • Innate Lymphoid Cell
  • Enhanced Antitumor Activity
NK cells are innate lymphoid cells that mediate potent anti-tumor responses against B cell malignancies in conjunction with anti-CD20 mAbs. ALT-803 is a superagonist IL-15 and dimeric IL-15Rα-IgG-Fc fusion protein that effectively trans-presents IL-15 and exhibits prolonged in vivo pharmacokinetics compared to rhIL-15. We hypothesized that ALT-803 will augment anti-CD20 mAb (rituximab)-directed NK cell ADCC against B cell lymphomas, facilitating NK cell-mediated lymphoma clearance. Short-term in vitro activation with ALT-803 (0.35-35 ng/mL) increased the expression of the cytotoxic effector protein granzyme B (p < 0.05) in human NK cells. ALT-803 also potentiated rituximab-directed NK cell ADCC against Raji (27% vs. 74%, E:T 25:1, p < 0.01) and Daudi (39% vs. 84%, E:T 2:1, p < 0.05) human B cell lymphoma lines. Moreover, activation of NK cells with ALT-803 significantly augmented CD20-specific ADCC against primary human follicular lymphoma cells in vitro (Figure 1, 11% vs. 33% at a 2.5:1 E:T ratio, p < 0.001). Animal models were employed to assess ALT-803 modulation of NK cell-mediated ADCC against B cell lymphoma in vivo. First, Daudi cells were engrafted into NK cell-competent SCID mice. Groups were treated with vehicle (day 15,18), rituximab (day 15,18), ALT-803 (day 15,18), or rituximab+ALT-803, and assessed for Daudi cell percentages in the BM at day 22. Mice treated with rituximab+ALT-803 combination therapy had significantly reduced Daudi cell burden in BM, compared to rituximab, ALT-803, or vehicle treatment (vehicle vs. ALT-803+rituximab, 38 ± 7% vs. 5 ± 8%, P = 0.005). The enhanced antitumor activity of the combination therapy was ALT-803 dose-dependent (p < 0.02 for 0.02-0.2 mg/kg ALT-803 + rituximab compared to rituximab alone). Furthermore, mice treated with ALT-803+rituximab had superior survival compared to ALT-803 or rituximab monotherapy (Figure 2, P < 0.05). In the second model, Raji B cells expressing luciferase were engrafted into immunodeficient NOD-SCID-γc-/- mice (day 0), and treated with primary human NK cells (day 3) plus vehicle, ALT-803 (0.05 mg/kg q3-4 days), rituximab (day 3), or ALT-803+rituximab. At day 16, ALT-803+rituximab exhibited a significant reduction in Raji signal compared to the control groups (p < 0.05). ALT-803 was well tolerated at all of the administered dose levels in combination with rituximab. Thus, ALT-803 represents an effective IL-15 receptor-agonist that augments NK cell cytotoxic potential and ADCC against malignant B cells in vitro, and significantly increases rituximab-triggered clearance of B cell lymphoma by NK cells in two in vivo models. Based on these findings, a Phase 1/2 clinical trial of ALT-803 plus rituximab is planned for patients with relapsed/refractory indolent NHLs.
Figure 1
Figure 1

ALT-803 enhances NK cell ADCC against primary follicular lymphoma. (A) Representative 4 hour flow-based ADCC assay demonstrating killing of CD19+ lymphoma cells at the indicated effector target ratios after 24 hours of stimulation with 35 ng/ml ALT-803 and 30 minute FL cell labeling with rituximab or control IgG1 monoclonal antibody. Effectors were purified (>95% CD56+CD3-) NK cells. (B) Summary data (N = 5 lymphoma sample targets, N = 15 normal NK cell donors, N = 5 independent experiments) showing the dose-dependent increase in mean ADCC enhanced by ALT-803. *p < 0.001

Figure 2
Figure 2

Alt-803+rituximab protects against lethal Daudi lymphoma challenge. Kaplan-Meir survival estimates of SCID mice injected iv with 1e7 Daudi lymphoma cells (day 0) and treated with vehicle (PBS). ALT-803 (day 15,18 0.05 mg/kg), rituximab (10 mg/kg day 15), or ALT-803+rituximab (day 15, 18). N = 7 mice per group. Significant (p < 0.05) survival improvement with ALT-803+rituximab compared to vehicle treatment group.

Authors’ Affiliations

(1)
Washington University School of Medicine, St Louis, USA
(2)
Altor BioScience Corporation, Miramar, USA

Copyright

© Rosario et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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