Enhancing the Functional Activity of Natural Killer Cells Against Myeloid Leukemia with the IL-15 Super-Agonist, ALT-803
Year: 2016
Type: article
Abstract: Strategies to optimize the anti-leukemia effect of allogeneic natural killer (NK) cell therapy include attempts to enhance NK cell activity, proliferation and survival in vivo. IL-2 is traditionally used to sustain allogeneic NK cells in vivo, but it leads to unwanted proliferation of regulatory T cells and suboptimal NK cell proliferation. IL-15 may be superior to IL-2, without the effect on regulatory T cells. ALT-803, a fusion of an IL-15 mutant and the IL-15Rα/Fc complex, has recently entered clinical trials as an immunomodulatory agent in cancer therapy. It exhibits >25 fold the biologic activity of IL-15. We hypothesized ALT-803 would augment activity of NK cells in vitro and in vivo. Human NK cells were expanded over a 21-day period in co-culture with irradiated K562 cells expressing membrane-bound IL-21. (Somanchi et al. JoVE 2011). IL-2 (50mU/mL) and/or ALT-803 (200ng/mL) was added to the culture. On Day 21, NK cells were phenotyped and tested for activity against OCI-AML3 cells. NSG mice (5/group) were non-lethally irradiated and each injected IV with 5 x106 OCI-AML3 leukemic cells. Two days later, each mouse received weekly NK cell infusions for 2 weeks. Mice that received NK cells expanded with IL2 got cytokine support with IL-2 (75kU IP thrice weekly). Mice infused with ALT-803 expanded cells (alone or in combination with IL2) received ALT-803 (0.2mg/kg IV weekly). One control OCI-AML3 group were infused weekly only with 2% FBS vehicle. Leukemic burden in each mouse was assessed by flow cytometry of bone marrow aspirates on day 28 when control mice were moribund. ALT-803 had no differential effect on the proliferation of the NK cells ex vivo as compared to IL-2. However, ALT-803 either alone or in combination with IL-2 resulted in a significant increase (30% increase, p<0.0001) in the cytotoxic activity of NK cells against leukemia cells as compared with IL-2 alone in vitro (Figure 1). In addition, NK cell expression of NKG2D and CD16 were significantly higher (p<0.001 for both) after ALT-803 exposure (Fig. 1). NKG2D is an NK cell surface activating receptor that engages stress ligands MICA and MICB on myeloid leukemia cells. In the murine OCI-AML model, ALT-803 expanded NK cells, with in vivo ALT-803, resulted in an 8-fold reduction in disease burden in the bone marrow (p<0.0001). Importantly the efficacy of NK cells in the ALT-803 injected mice was significantly higher (3-fold, p= 0.0447) than IL-2 treated mice (Fig. 2). Our results suggest that ALT-803 during ex-vivo expansion of NK cells and in vivo results in their increased activation and anti-leukemic benefit compared to IL-2. Future studies to test larger panels of leukemia cells as well as other cancer cell lines are currently in progress. It is hoped that this work will lead to an improvement in the efficacy of adoptively transferred NK cells for AML patients due to an improvement in survival and activity of the NK cells.Figure 2ALT-803 injected mice exhibit enhanced afficacy of adoptively transferred NK cells in a mouse AML model system.View Large Image Figure ViewerDownload Hi-res image Download (PPT)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2508563773