BTK抑制剂治疗联合靶向CD19嵌合抗原受体的T细胞（CART19）提... - 中国病毒学论坛|我们一直在坚持！

The Addition of the BTK inhibitor Ibrutinibto Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responsesagainst Mantle Cell Lymphoma.

Responses to therapy with chimeric antigen receptor Tcells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle celllymphoma (MCL) represents a B-cell malignancy that remains incurable despitenovel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019therapy are scant. Using MCL as a model, we sought to build upon the outcomesfrom CTL019 and from ibrutinib therapy by combining these in a rational manner.

MCL cell lines and primary MCL samples were combinedwith autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of thecombination was studied in vitro and in mouse xenograft models.

MCL cells strongly activated multiple CTL019 effectorfunctions, and MCL killing by CTL019 was further enhanced in the presence ofibrutinib. In a xenograft MCL model, we showed superior disease control in theCTL019- as compared to ibrutinib-treated mice (median survival not reachedversus 95 days, p<0.005) but most mice receiving CTL019 monotherapy eventuallyrelapsed. Therefore, we added ibrutinib to CTL019 and showed that 80-100% ofmice in the CTL019+ibrutinib arm and 0-20% of mice in the CTL019 arm,respectively, remained in long-term remission (p<0.05).

Combining CTL019 with ibrutinib represents a rationalway to incorporate two of the most recent therapies in MCL. Our findings pavethe way to a two-pronged therapeutic strategy in patients with MCL and othertypes 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

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。

MCL细胞系和初始的MCL样本联合使用自体或者正常供体的CD19CAR-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。

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)。

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。