BTK抑制剂治疗联合靶向CD19嵌合抗原受体的T细胞（CART19）提高了对套细胞淋巴瘤的反应

技术资料下载地址：http://www.ncbi.nlm.nih.gov/pubmed/26819453
文献来源：Clin Cancer Res

The Addition of the BTK inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma.
Abstract
PURPOSE:
Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner.
EXPERIMENTAL DESIGN:
MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models.
RESULTS:
MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared to ibrutinib-treated mice (median survival not reached versus 95 days, p<0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80-100% of mice in the CTL019+ibrutinib arm and 0-20% of mice in the CTL019 arm, respectively, remained in long-term remission (p<0.05).
CONCLUSIONS:
Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma.

BTK抑制剂治疗联合靶向CD19嵌合抗原受体的T细胞（CART19）提高了对套细胞淋巴瘤的反应
摘要
目的:
利用嵌合抗原受体修饰的T细胞识别CD19(CART19, CTL019)的治疗效果可能会由于不同的组织而不一样。套细胞淋巴瘤（MCL）是B细胞恶性肿瘤的一种，尽管开发了BTK抑制剂治疗的新疗法，但是仍然无法治愈该疾病，而来自CTL019疗法的数据则很少。使用MCL为模型，我们试图将CTL019和ibrutinib治疗相结合，来考察治疗的疗效。
试验设计：
MCL细胞系和初始的MCL样本联合使用自体或者正常供体的CD19 CAR-T细胞和BTK抑制剂ibrutinib进行培养。我们对体外和小鼠异种模型的组合治疗进行了研究。
结果：
MCL细胞强烈的激活了CTL019细胞的功能，在BTK抑制剂ibrutinib存在的前提下，MCL的的灭活效果得到了进一步的加强。在一个异种移植MCL的模型体内，我们发现CTL019 CAR-T细胞治疗与BTK抑制剂ibrutinib相比，具有更好的疾病控制能力，但是接收CTL019治疗的小鼠最终还是复发了该疾病。因此，我们增加了ibrutinib到CTL019中，CTL019+ibrutinib小鼠模型和CTL019小鼠模型的有效率分别是80-100%和0-20%，保持长期的缓解率(p<0.05)。
结论：
将CTL019和ibrutinib结合代表着一个理性的方式来治疗MCL。我们的发现是一个MCL患者和其他B细胞恶性淋巴瘤的双重治疗方式。

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