Abstract
Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and remains incurable despite recent therapeutic advances. Natural killer (NK) cells have potent anti-cancer effects, but efforts to use NK cell therapy in CLL have been limited by poor NK cell growth and anti-leukemia activity. We sought to determine if stimulating NK cells ex vivo with K562-based feeder cells expressing membrane-bound IL-21 (mbIL-21) (Denman et al., 2012) could overcome the limitations of prior techniques to create an effective therapy for CLL. Our data demonstrate that healthy donor-derived mbIL-21 expanded NK cells have increased antibody-dependent cellular cytotoxicity (ADCC) and direct cytotoxicity (DC; without targeting antibody) against CLL cell lines. This technique can also overcome CLL-induced NK suppression – CLL patient-derived NK cells expanded equally and were as potent as normal donor-derived NKs, including against both allogeneic and autologous CLL tumor cells. CLL tumor cells are not susceptible to DC but are very vulnerable to ADCC with anti-CD20 antibodies (rituximab or obinutuzumab). The lack of direct cytotoxicity of tumor cells was correlated to low NK:CLL quantitative conjugate formation, suggesting a lack of tumor target recognition. Blocking antibodies to FasL, TNFα, and TRAIL show that only TRAIL contributes modestly to anti-CLL tumor cytotoxicity, while application of folimycin demonstrates that perforin/granzyme release is the major mechanism of cytotoxicity. In vivo, treatment with expanded NK cells plus obinutuzumab significantly prolongs survival in the OSU-CLL human xenograft model. Based on these data, we are planning a clinical trial of mbIL-21 expanded NK cells plus obinutuzumab in CLL patients.
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