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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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处肝转移，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。

出自爱康得生物技术