A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect.
A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect.
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DOI：
10.2147/jhc.s136652
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发表时间：
2017
影响因子：
4.1
通讯作者：
Salazar AM
中科院分区：
文献类型：
--
作者：
de la Torre AN;Contractor S;Castaneda I;Cathcart CS;Razdan D;Klyde D;Kisza P;Gonzales SF;Salazar AM
目的：确定一种通过结合非致命性放射、局部区域治疗和瘤内注射以及全身性给予有效的Toll样受体(TLR)免疫佐剂来增强肝细胞癌(HCC)局部免疫治疗的安全性。不符合肝移植或手术条件的肝癌患者接受以下治疗：1)3Gy2Gy局部非致命性照射以增加肿瘤抗原表达；2)瘤内/瘤周注射TLR3激动剂多肌苷-多胞苷多聚赖氨酸羧甲基纤维素(Poly-ICLC)，通过局部局部治疗在肿瘤微环境中诱导免疫“危险”反应；3)肌肉内注射Poly-ICLC全身增强免疫。主要终点是安全性和耐受性；次要终点是6个月、1年和2年的无进展生存期(PFS)和总生存期(OS)。18名不适合手术或肝移植的肝细胞癌患者接受了治疗。除1例与栓塞术相关的严重不良事件外，所有事件均为≤II级。6个月、12个月和24个月的PFS分别为66%、39%和28%。总的1年生存率为69%，2年生存率为38%。在60岁的患者中，2年生存率为62.5%，而在60岁的患者中为11.1%(P<；0.05)。部分患者PFS和OS延长。肝癌患者瘤内注射TLR3激动剂PolyICLC联合局部非致命性放射治疗和局部区域治疗是安全和可耐受的。进一步的工作正在进行中，以评估这种方法是否与单独局部区域治疗相比提高了存活率，并表征了抗癌免疫的变化。
To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant. Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic “danger” response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years. Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS. Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity.