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HITM-SURE:利用压力增强药物递送的针对转移性肝癌的免疫治疗的 Ib 期抗 CEA CAR-T 研究

HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery.

机构信息

Surgery, Roger Williams Medical Center, Providence, Rhode Island, USA

Medicine, Roger Williams Medical Center, Providence, Rhode Island, USA.

出版信息

J Immunother Cancer. 2020 Aug;8(2). doi: 10.1136/jitc-2020-001097.

Abstract

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.

摘要

近年来,细胞治疗技术在血液恶性肿瘤方面取得了令人瞩目的成果。嵌合抗原受体 T 细胞(CAR-T)治疗实体瘤的效果则不尽如人意。实体瘤带来了一些与血液癌症不同的挑战,包括肿瘤内高压和 CAR-T 向疾病部位的有效运输。新的给药方法可能使 CAR-T 疗法应用于实体瘤恶性肿瘤。一名患有胰腺腺癌肝转移的患者接受了针对癌胚抗原(CEA)的 CAR-T 治疗。此前我们报道过,压力增强药物输送(PEDD)可将 CAR-T 递送至肝转移灶的效率提高 5.2 倍。通过 PEDD 技术,采用肝动脉输注(HAI)的方式局部给予三剂抗 CEA CAR-T,以优化治疗指数。白细胞介素-2 通过连续静脉输注全身给予,以支持 CAR-T 在体内的作用。HAI 给予抗 CEA CAR-T 与任何 3 级以上的严重不良事件(SAE)无关,也没有发生靶外/肿瘤 SAE。CAR-T 治疗后,正电子发射断层扫描-CT 显示肝脏内完全代谢缓解,持续 13 个月。该缓解伴随着肿瘤标志物血清水平的正常化和治疗后肿瘤标本中大量的 CAR+细胞。该报告的结果显示了局部给予 CAR-T 治疗该适应证的生物学活性和安全性,该适应证在免疫肿瘤学方面迄今为止的成功率有限。进一步的研究将确定如何将 HAI 给予 CAR-T 纳入肝转移患者的多学科治疗计划。临床试验编号,NCT02850536。

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