IL-21 enhances rituximab-mediated killing of B-lymphoma cell lines in vitro and in vivo

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2581 Background: IL-21 is an IL-2 family cytokine expressed by activated CD4+ T cells. It has potent immunomodulatory activities on a number of cell types and has shown significant anti-tumor activity in preclinical animal studies. Phase I studies in metastatic melanoma and renal cell carcinoma are intended to commence in the first half of 2004. For NK cells, IL-21 promotes activated characteristics, including enhanced cytolytic activity, IFN-γ production, and expression of cell surface CD16. To examine the possible consequences of IL-21 stimulation on antibody mediated NK effector functions, we carried out in vitro and in vivo studies using rituximab/CD20+ lymphoma as a model system. Methods: NK cells were prepared by negative selection from peripheral blood mononuclear cells of healthy donors, cultured for 3 days ± IL-21, and cytolytic activity was measured against human B-lymphoma cell targets in the presence or absence of rituximab. Additionally, IFN-γ production by NK cells cultured with IL-21 and plate bound IgG was assayed by ELISA. To assess the combined effects of IL-21 and rituximab in vivo, SCID mice (n=10) were injected IV with 106 HS Sultan cells and treated with vehicle, IL-21 (5 mg/kg QD, days 1–5), rituximab (1 mg/kg Q 4th day x 5, starting day 3) or a combination of IL-21 and rituximab. Results: IL-21 enhanced IFN-γ production by NK cells costimulated with plate bound IgG in a dose dependent manner. Compared to control NK cultures, pre-exposure to IL-21 significantly increased lytic activity of NK cells on human B-lymphoma cell targets in the presence of rituximab. Similarly, treatment of HS Sultan bearing mice with a combination of IL-21 and rituximab resulted in significantly increased survival compared to treatment with rituximab alone (70% versus 10% at day 90; p<.004, logrank). Conclusions: In both in vitro and in vivo studies, IL-21 synergistically enhanced rituximab mediated cytotoxicity. These data suggest that antibody mediated NK cell effector functions are augmented by IL-21, and that IL-21 may be clinically useful in the context of antibody based cancer therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ZymoGenetics ZymoGenetics