Abstract P3-05-04: An IL-15 superagonist enhances antibody-dependent cell-mediated cytotoxicity against breast cancer cells regardless of FCGR3A (CD16) genotype and rescues NK cell from TGF-β1-induced immunosuppression
Authors: Fujii R , Wong HC , Schlom J , Hodge JW 
Published: February 2018

Abstract
It has been reported that the Natural killer (NK) cell with FCGR3A (CD16a) V genotype is associated with enhanced clinical response to IgG1 monoclonal Ab (mAb) therapy such as trastuzumab, rituximab and cetuximab (1,2), suggesting a role of antibody-dependent cell-mediated cytotoxicity (ADCC) induced by NK cells. NK cells express three types of polymorphism of CD16; FcγRIIIa-158 VV, VF, FF, which are derived from the genotype of FCGR3A. It is a clinical challenge to improve the outcome in patients with FCGR3A 158FF genotype whose NK cells have lower affinity to mAb and mediate poor ADCC activity. The IL-15 superagonist/IL-15Rα-Fc fusion complex (ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, inducing their expansion, cytotoxity, and ADCC against B cell lymphoma (3, 4, 5).
Here, we examined the effect of ALT803 on NK cell-mediated ADCC activity by the the anti-HER2 IgG1 mAb trastuzumab in HER2+ cell lines (SKBR3, BT474, MDA-MB-453). In addition, we used the anti-epidermal growth factor receptor(EGFR) IgG1 mAb cetuximab in EGFR positive TNBC cell lines (MDA-MB-231, SUM149, BT549). Finally, we examined the anti-PD-L1 IgG1 mAb avelumab was used for PD-L1 positive breast cancer cell lines (MDA-MB-231, BT549). Trastuzumab, cetuximab, and avelumab all significantly increased NK cell-induced lysis via ADCC. ALT803 significantly further increased both NK induced lysis and ADCC activity in all the cell lines. There was a significant positive correlation for the mean of ADCC lysis induced by NK cells from three FF (21%), three VF (33%), three VV (45%) donors. ALT803 significantly increased the mean of ADCC lysis by NK cells from all donors of each genotype to the same extent. ALT803 increased the expression of NK cell-activating receptors and cytotoxic granules regardless of the genotype of NK cell FCGR3A in terms VV, VF, or FF.
We further examined the potential of ALT803 for NK cell-cytotoxicity suppressed by TGF-β1 which is one of the main barriers to immunity in the tumor microenvionment (TME). NK cells treated with TGF-β1 showed lower expression of activating receptors and cytotoxic granules, culminating in decreased lysis of MDA-MB231. ALT803 inhibited TGF-β1 from down-regulating the expression of NK cell-activating receptors and cytotoxic granules, and from suppressing the cytotoxicity of NK cells to MDA-MB231.
In conclusion, the IL-15 superagonist ALT803 can potentially increase the clinical benefit of ADCC-based mAb therapy for breast cancer patients, regardless of the genotype of FCGR3A. Moreover, ALT803 prevented NK cell-cytotoxity from TGF-β1-induced suppression, providing a rationale for ALT803 therapy to overcome TME-mediated immunosuppression.
References
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(5) Rosario et. al. Clin. Cancer Res. 2016; 22(3)
Citation Format: Fujii R, Wong HC, Schlom J, Hodge JW. An IL-15 superagonist enhances antibody-dependent cell-mediated cytotoxicity against breast cancer cells regardless of FCGR3A (CD16) genotype and rescues NK cell from TGF-β1-induced immunosuppression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-04.