Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.
Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.
复制标题
第一阶段的肝免疫疗法用于转移研究的动脉内嵌合抗原受体修饰的T细胞疗法用于CEA+肝转移。
DOI：
10.1158/1078-0432.ccr-14-1421
复制
发表时间：
2015-07-15
期刊：
影响因子：
--
通讯作者：
Junghans RP
中科院分区：
文献类型：
--
作者：
Katz SC;Burga RA;McCormack E;Wang LJ;Mooring W;Point GR;Khare PD;Thorn M;Ma Q;Stainken BF;Assanah EO;Davies R;Espat NJ;Junghans RP
嵌合抗原受体修饰的T细胞（CAR-T）在早期临床试验中表现出令人鼓舞的结果。CAR-T技术成功适应CEA表达腺癌肝转移（LM），这是胃肠道癌症患者死亡的主要原因，尚未实现。我们试图通过经皮肝动脉输注（HAI）测试抗CEA CAR-T的肝内递送。我们进行了一项I期试验，以测试CEA+ LM患者中CAR-T的HAI。6名患者完成了方案，3名患者以剂量递增方式单独接受抗CEA CAR-T HAI（108、109和1010个细胞）。我们用最大计划CAR-T HAI剂量（1010个细胞X 3）沿着全身性IL 2支持治疗另外3名患者。4例患者的LM超过10例，患者在入组前平均接受了2.5线常规全身治疗。没有患者发生与CAR-T HAI相关的3级或4级不良事件。1例患者在CAR-T HAI后23个月仍存活，病情稳定，5例患者死于疾病进展。在接受全身IL 2支持的队列中的患者中，CEA水平从基线降低37%（范围19-48%）。6例患者中有4例活检显示LM坏死或纤维化增加。血清IFNγ水平升高与IL 2给药和CEA降低相关。我们已经证明了抗CEA CAR-T HAI的安全性，在具有大肿瘤负荷的重度预治疗人群中具有令人鼓舞的临床活性信号。CAR-T HAI用于LM的进一步临床试验是必要的。
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 (LM), 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 (HAI). We conducted a phase I trial to test HAI of CAR-T in patients with CEA+ LM. Six patients completed the protocol, and 3 received anti-CEA CAR-T HAIs alone in dose-escalation fashion (108, 109, and 1010 cells). We treated an additional 3 patients with the maximum planned CAR-T HAI dose (1010 cells X 3) along with systemic IL2 support. Four patients had more than 10 LM and patients received a mean of 2.5 lines of conventional systemic therapy prior to 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 LM necrosis or fibrosis in 4 of 6 patients. Elevated serum IFNγ levels correlated with IL2 administration and CEA decreases. We have demonstrated the safety of anti-CEA CAR-T HAIs with encouraging signals of clinical activity in a heavily pre-treated population with large tumor burdens. Further clinical testing of CAR-T HAIs for LM is warranted.