Romidepsin alone or in combination with anti-CD20 chimeric antigen receptor expanded natural killer cells targeting Burkitt lymphoma in vitro and in immunodeficient mice
Romidepsin alone or in combination with anti-CD20 chimeric antigen receptor expanded natural killer cells targeting Burkitt lymphoma in vitro and in immunodeficient mice
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DOI：
10.1080/2162402x.2017.1341031
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Cairo, Mitchell S.
中科院分区：
文献类型：
--
作者：
Chu, Yaya;Yahr, Ashlin;Cairo, Mitchell S.
迫切需要促进替代靶向治疗策略的开发，以改善儿童、青少年和成人复发性/难治性新发成熟B细胞（CD 20）非霍奇金淋巴瘤（包括伯基特淋巴瘤（BL））的结局或避免化疗耐药性。罗米地辛是一种组蛋白去乙酰化酶抑制剂（HDACi），已被用于治疗皮肤T细胞淋巴瘤。我们已经证明了抗CD 20嵌合抗原受体（CAR）修饰的扩增的外周血自然杀伤细胞（exPBNK）对利妥昔单抗敏感和耐药BL的显著抗肿瘤作用。该研究检查了单独的罗米地辛和与抗CD 20 CAR exPBNK组合在体外和体内针对利妥昔单抗敏感性和耐药性BL的抗肿瘤活性。我们发现罗米地辛在体外显著抑制利妥昔单抗敏感和耐药BL细胞增殖（P < 0.001），并诱导利妥昔单抗敏感Raji细胞死亡（P < 0.001）和利妥昔单抗耐药Raji-2 R和Raji-4 RH细胞周期阻滞（P < 0.001）。与体外观察一致，我们还发现罗米地辛显著抑制BL异种移植NSG小鼠中利妥昔单抗敏感性和抗性BL的生长。我们还证明，罗米肽在利妥昔单抗敏感和耐药的BL细胞中显著诱导自然杀伤组2成员D（NKG 2D）配体云母/B的表达（P < 0.001），导致通过NKG 2D增强exPBNK的体外细胞毒性。最后，我们观察到罗米地辛和抗CD 20 CAR exPBNK的组合在体外显著诱导BL细胞的细胞死亡，降低肿瘤负荷并提高人源化BL异种移植NSG小鼠的存活率（p < 0.05）。我们的数据表明，罗米地辛是一种活性HDAC抑制剂，其还增强了针对利妥昔单抗敏感性和耐药性BL的扩展的NK和抗CD 20 CAR exPBNK活性。
Facilitating the development of alternative targeted therapeutic strategies is urgently required to improve outcome or circumvent chemotherapy resistance in children, adolescents, and adults with recurrent/refractory de novo mature B-cell (CD20) non-Hodgkin lymphoma, including Burkitt lymphoma (BL). Romidepsin, a histone deacetylase inhibitor (HDACi), has been used to treat cutaneous T-cell lymphoma. We have demonstrated the significant anti-tumor effect of anti-CD20 chimeric antigen receptor (CAR) modified expanded peripheral blood natural killer (exPBNK) against rituximab-sensitive and -resistant BL. This study examined the anti-tumor activity of romidepsin alone and in combination with anti-CD20 CAR exPBNKs against rituximab-sensitive and -resistant BL in vitro and in vivo. We found that romidepsin significantly inhibited both rituximab-sensitive and -resistant BL cell proliferation in vitro (P < 0.001) and induced cell death in rituximab-sensitive Raji (P < 0.001) and cell cycle arrest in rituximab-resistant Raji-2R and Raji-4RH (P < 0.001). Consistent with in vitro observations, we also found romidepsin significantly inhibited the growth of rituximab-sensitive and -resistant BL in BL xenografted NSG mice. We also demonstrated that romidpesin significantly induced the expression of Natural Killer Group 2, Member D (NKG2D) ligands MICA/B in both rituximab-sensitive and -resistant BL cells (P < 0.001) resulting in enhancement of exPBNK in vitro cytotoxicity through NKG2D. Finally, we observed the combination of romidepsin and anti-CD20 CAR exPBNK significantly induced cell death in BL cells in vitro, reduced tumor burden and enhanced survival in humanized BL xenografted NSG mice (p < 0.05). Our data suggests that romidepsin is an active HDAC inhibitor that also potentiates expanded NK and anti-CD20 CAR exPBNK activity against rituximab-sensitive and -resistant BL.