Ibrutinib增强了嵌合抗原受体修饰的T细胞的植入以及其对白...

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技术资料下载地址: http://www.ncbi.nlm.nih.gov/pubmed/26813675

文献来源: Blood.

Ibrutinibenhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.

Anti-CD19chimeric antigen receptor (CAR) T-cell therapy is highly promising, butrequires robust T-cell expansion and engraftment. A T-cell defect in chroniclymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivoexpansion and response to CAR T-cells. Toevaluate the effect of ibrutinib treatment on the T-cell compartment in CLL asit relates to CAR T-cell generation, we examinedthe phenotype and function of T-cells in a cohort of CLL patients during theircourse of treatment with ibrutinib. We found that five or more cycles ofibrutinib therapy improved the expansion of CD19-directed CAR T-cells (CTL019), in association with decreasedexpression of the immunosuppressive molecules PD1 on T-cells and CD200 on B-CLLcells. In support of these findings, we observed that three CLL patients whohad been treated with ibrutinib for at least one year at the time of T-cellcollection had improved ex vivo and in vivo CTL019 expansion, which correlatedpositively together and with clinical response. Finally, we show that ibrutinibexposure does not impair CAR T-cell function invitro and in fact improves CAR T-cellengraftment, tumor clearance and survival in human xenograft models ofresistant acute lymphocytic leukemia (ALL) and CLL when administeredconcurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trialswith combination therapy are warranted. Finally, our studies demonstrate thatimproved T-cell function may also contribute to the efficacy of ibrutinib inCLL.

Ibrutinib增强了嵌合抗原受体修饰的T细胞的植入以及其对白血病的有效性

CD19 CAR-T细胞治疗前途非常有希望，但是需要有效的T细胞扩增和植入。为了评估Ibrutinib对CAR-T细胞在CLL中的治疗效果，我们在一组CLL病人的治疗过程中采用了ibrutinib并检测了CAR-T细胞的表型以及T细胞的功能。我们发现，通过5个或者更多的ibrutinib循环治疗，能够增加CD19 CAR-T细胞的扩增，并且能够减少免疫抑制分子PD-1在T细胞和CD200在B细胞中的表达。为了支持这样的发现，我们观察了三位CLL患者，他们接受了ibrutinib治疗至少1年，同时发现在体内和体外，CTL019的扩增能力都得到了提升，这会有更好的临床效果。最后，我们发现ibrutinib的使用不仅不会影响到CAR-T细胞在体内的功能，事实上会增加CAR-T细胞的植入能力、肿瘤清楚能力和其在人急性淋巴细胞白血病和CLL异种模型中的存活。我们的合作研究表明，ibrutinib能够增强CAR-T细胞的功能，并且暗示联合治疗的方案是比较必要的。最后，我们的研究表明，使用ibrutinib能够增加CAR-T细胞治疗的治疗效果。

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