γδ T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody
γδ T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody
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DOI：
10.3324/haematol.2010.029520
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发表时间：
2011-03-01
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影响因子：
--
通讯作者：
Rossi, Jean-Francois
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作者：
Braza, Mounia Sabrina;Klein, Bernard;Rossi, Jean-Francois
背景抗CD 20单克隆抗体是治疗滤泡性淋巴瘤的主要药物，主要通过补体介导的细胞毒作用和抗体依赖的细胞毒作用发挥作用。设计和方法我们研究了V γ 9V δ 2 T细胞对滤泡性淋巴瘤细胞的细胞毒性活性，以及这种杀伤是否可以通过用抗CD 20单克隆抗体促进抗体依赖性细胞毒性而增加，特别是II型糖工程化抗CD 20。V γ 9V delta 2 T细胞在存在溴醇焦磷酸盐（Phosphostim）和白细胞介素-2的情况下进行体外扩增，并在存在或不存在三种抗CD 20单克隆抗体的情况下通过流式细胞术细胞毒性T淋巴细胞测定法评估它们杀死滤泡性淋巴瘤原代细胞或细胞系的能力：无岩藻糖基化GA 101、嵌合利妥昔单抗或人源化奥法木单抗。当与滤泡性淋巴瘤原代细胞或细胞系在存在或不存在三种抗-CD 20单克隆抗体的情况下共培养时，这些细胞释放穿孔素/颗粒酶和分泌干扰素-γ的能力也通过CD 107 a染色和Elispot测定来评估。2个扩增的V γ 9V δ 2 T细胞对原发性滤泡性淋巴瘤细胞具有细胞毒性，并且GA 101显著增加了它们的细胞毒性潜力，II型糖工程化抗CD 20单克隆抗体，以及在较小程度上，利妥昔单抗和奥法木单抗。增加的细胞毒性与增加分泌的穿孔素/颗粒酶和干扰素-gamma. ConclusionsIn体外扩大的V γ 9V δ 2 T细胞有效地杀死原发性滤泡性淋巴瘤细胞和表达CD 16;抗CD 20单克隆抗体，特别是GA 101，显着增加扩大的V γ 9V δ 2 T细胞的细胞毒性活性。这些临床前结果促进了使用V γ 9V δ 2 T细胞和抗CD 20单克隆抗体的这种抗体依赖性细胞毒性性质的临床试验的发展。
BackgroundAnti-CD20 monoclonal antibodies are major therapeutic agents for patients with follicular lymphoma and work through complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. Optimization of antibody-dependent cellular cytotoxicity, in particular by amplifying its effectors, could further increase the efficacy of anti-CD20 monoclonal antibodies.Design and MethodsWe investigated the cytotoxic activity of V gamma 9V delta 2 T cells against follicular lymphoma cells and whether this killing could be increased by promoting antibody-dependent cellular cytotoxicity with anti-CD20 monoclonal antibodies, in particular a type-II glycoengineered anti-CD20. V gamma 9V delta 2 T cells were expanded in vitro in the presence of bromohydrin pyrophosphate (Phosphostim) and interleukin-2 and their ability to kill follicular lymphoma primary cells or cell lines was evaluated by flow cytometry cytotoxic T-lymphocyte assays in the presence or absence of three anti-CD20 monoclonal antibodies: the afucosylated GA101, the chimeric rituximab or the humanized ofatumumab. The ability of these cells to release perforin/granzyme and secrete interferon-gamma when co-cultured with follicular lymphoma primary cells or cell lines in the presence or not of the three anti-CD20 monoclonal antibodies was also evaluated by CD107a staining and Elispot assays.ResultsPhosphostim and interleukin-2 expanded V gamma 9V delta 2 T cells were cytotoxic to primary follicular lymphoma cells and their cytotoxic potential was dramatically increased by GA101, a type II glycoengineered anti-CD20 monoclonal antibody, and to a lesser extent, by rituximab and ofatumumab. The increased cytotoxicity was associated with increased secretion of perforin/granzyme and interferon-gamma.ConclusionsIn-vitro expanded V gamma 9V delta 2 T cells efficiently kill primary follicular lymphoma cells and express CD16; anti-CD20 monoclonal antibodies, in particular GA101, dramatically increase the cytotoxic activity of expanded V gamma 9V delta 2 T cells. These preclinical results prompt the development of clinical trials using this antibody dependent cellular cytotoxicity property of V gamma 9V delta 2 T cells and anti-CD20 monoclonal antibodies.