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动脉内CAR-T细胞治疗技术对CEA阳性转移肝癌细胞的研究

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发表于 2016-1-8 11:12:53 | 显示全部楼层 |阅读模式
Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.
PURPOSE:
Chimeric antigen receptor-modified T cells (CAR-T) have demonstrated encouraging results in early-phase clinical trials. Successful adaptation of CAR-T technology for CEA-expressing adenocarcinoma liver metastases, a major cause of death in patients with gastrointestinal cancers, has yet to be achieved. We sought to test intrahepatic delivery of anti-CEA CAR-T through percutaneous hepatic artery infusions (HAIs).
EXPERIMENTAL DESIGN:
We conducted a phase I trial to test HAI of CAR-T in patients with CEA(+) liver metastases. Six patients completed the protocol, and 3 received anti-CEA CAR-T HAIs alone in dose-escalation fashion (10(8), 10(9), and 10(10) cells). We treated an additional 3 patients with the maximum planned CAR-T HAI dose (10(10) cells × 3) along with systemic IL2 support.
RESULTS:
Four patients had more than 10 liver metastases, and patients received a mean of 2.5 lines of conventional systemic therapy before enrollment. No patient suffered a grade 3 or 4 adverse event related to the CAR-T HAIs. One patient remains alive with stable disease at 23 months following CAR-T HAI, and 5 patients died of progressive disease. Among the patients in the cohort that received systemic IL2 support, CEA levels decreased 37% (range, 19%-48%) from baseline. Biopsies demonstrated an increase in liver metastasis necrosis or fibrosis in 4 of 6 patients. Elevated serum IFNγ levels correlated with IL2 administration and CEA decreases.
CONCLUSIONS:
We have demonstrated the safety of anti-CEA CAR-T HAIs with encouraging signals of clinical activity in a heavily pretreated population with large tumor burdens. Further clinical testing of CAR-T HAIs for liver metastases is warranted.
动脉内CAR-T细胞治疗技术对CEA阳性转移肝癌细胞的研究
目的:
CAR-T细胞治疗技术已经在早期的临床试验中展现了激动人心的结果。CAR-T细胞技术对抗表达CEA的胰腺癌肝转移,一种胃肠道癌症患者死亡的主要原因,已经完成了试验。通过经皮的肝动脉注射,我们试图检测靶向CEA CAR-T细胞在肝脏内的传递。
试验设计:
我们进行了一项I期临床试验,对CEA阳性肝转移患者进行HAI的测试。6例病人完成了协议,3位患者接受了靶向CEA CAR-T细胞经皮肝动脉注射以一个递增的细胞剂量(10(8), 10(9), 和10(10)细胞数)。我们对其他三位患者以一个最大的CAR-T细胞数量(10(10) 细胞数 × 3)与IL-2一起,通过肝脏动脉传递注射。
结果:
四名患者有超过10肝转移,试验前,患者接受了常规全身治疗。没有患者出现与CAR-T感染相关3级或4的不良事件。一个病人仍然活着,病情稳定在CAR-T治疗23个月后CAR-T医院感染相关,5例死于癌症的疾病进展。在接受全身IL2注射的患者中,CEA水平从基线下降37%区间,19% - 48%)。活检显示6例患者中有4例肝转移坏死或纤维化增加。血清IFN-γ的水平与γIL2的管理和CEA的下降有关。
结论:
我们已经证实了靶向CEA CAR-T 经皮肝动脉传递的安全性。将来,临床上对CAR-T 细胞的HAI治疗肝转移癌的进一步的测试是必要的。
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