Abstract
<div>Abstract<p><b>Purpose:</b> Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα–Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti–CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC).</p><p><b>Experimental Design:</b> We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells <i>in vitro</i> and <i>in vivo</i>. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary <i>in vivo</i> mouse models were used, which included human NK-cell xenografts in NOD/SCID-γ<sub>c</sub><sup>−/−</sup> mice.</p><p><b>Results:</b> We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNγ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct <i>in vivo</i> B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC.</p><p><b>Conclusions:</b> ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses <i>in vitro</i> and <i>in vivo</i>, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma. <i>Clin Cancer Res; 22(3); 596–608. ©2015 AACR</i>.</p></div>
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