Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia
Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia
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DOI：
10.1182/blood-2015-11-679134
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发表时间：
2016-03-03
期刊：
影响因子：
20.3
通讯作者：
Maus, Marcela V.
中科院分区：
文献类型：
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作者：
Fraietta, Joseph A.;Beckwith, Kyle A.;Maus, Marcela V.
抗CD19嵌合抗原受体(CAR)T细胞治疗前景看好，但需要强大的T细胞扩增和植入。慢性淋巴细胞性白血病(CLL)患者由于疾病和/或治疗导致的T细胞缺陷损害了细胞的体外扩增和对CART细胞的反应。为了评估伊布鲁替尼治疗对慢性淋巴细胞性白血病患者T细胞亚群的影响，我们检测了一组慢性淋巴细胞性白血病患者在伊布鲁替尼治疗过程中T细胞的表型和功能。我们发现，-gt；=5个周期的ibrutinib治疗促进了CD19导向的CART细胞(CTL019)的扩张，同时降低了T细胞上免疫抑制分子程序性细胞死亡1和B-CLL细胞上CD200的表达。为了支持这些发现，我们观察到，在T细胞采集时接受伊布鲁替尼治疗1年的3名CLL患者在体外和体内的CTL019扩增情况都有所改善，这与临床反应呈正相关。最后，我们发现，伊布鲁替尼在体外不会损害CAR T细胞的功能，但当同时给药时，确实可以改善CAR T细胞的植入、肿瘤清除和人类耐药急性淋巴细胞白血病和CLL异种移植模型的存活率。我们的集体研究结果表明，伊布鲁替尼可增强CAR T细胞功能，并提示联合治疗的临床试验是必要的。我们的研究表明，改善T细胞功能也可能有助于伊布鲁替尼治疗慢性淋巴细胞性白血病的疗效。这些试验在www.Clinicaltrials.gov上注册为#NCT01747486、#NCT01105247和#NCT01217749。
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivoexpansionand response to CART cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CART-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that >= 5 cycles of ibrutinib therapy improved the expansion of CD19-directed CART cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for >= 1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749.