Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma

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• 作者：Sarah Oelsner¹ ; ^* ; Miriam E. Friede¹ ; ^* ; Congcong Zhang¹ ; ^* ; Juliane Wagner² ; ³ ; Susanne Badura⁴ ; Peter Bader² ; Evelyn Ullrich² ; ³ ; Oliver G. Ottmann⁵ ; Hans Klingemann⁶ ; Torsten Tonn⁷ ; Winfried S. Wels¹ ; ⁸ ; ^{wels@gsh.uni-frankfurt.de}
• 关键词：adoptive immunotherapy ; B-cell malignancies ; CD19 ; chimeric antigen receptor ; natural killer cells
• 刊名：Cytotherapy
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：19
• 期：2
• 页码：235-249
• 全文大小：2684 K
• 卷排序：19

文摘

Natural killer (NK) cells can rapidly respond to transformed and stressed cells and represent an important effector cell type for adoptive immunotherapy. In addition to donor-derived primary NK cells, continuously expanding cytotoxic cell lines such as NK-92 are being developed for clinical applications.MethodsTo enhance their therapeutic utility for the treatment of B-cell malignancies, we engineered NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors (CARs) that target CD19 and contain human CD3ζ (CAR 63.z), composite CD28-CD3ζ or CD137-CD3ζ signaling domains (CARs 63.28.z and 63.137.z).ResultsExposure of CD19-positive targets to CAR NK-92 cells resulted in formation of conjugates between NK and cancer cells, NK-cell degranulation and selective cytotoxicity toward established B-cell leukemia and lymphoma cells. Likewise, the CAR NK cells displayed targeted cell killing of primary pre-B-ALL blasts that were resistant to parental NK-92. Although all three CAR NK-92 cell variants were functionally active, NK-92/63.137.z cells were less effective than NK-92/63.z and NK-92/63.28.z in cell killing and cytokine production, pointing to differential effects of the costimulatory CD28 and CD137 domains. In a Raji B-cell lymphoma model in NOD-SCID IL2R γnull mice, treatment with NK-92/63.z cells, but not parental NK-92 cells, inhibited disease progression, indicating that selective cytotoxicity was retained in vivo.ConclusionsOur data demonstrate that it is feasible to generate CAR-engineered NK-92 cells with potent and selective antitumor activity. These cells may become clinically useful as a continuously expandable off-the-shelf cell therapeutic agent.