PDF(Pubmed)
Abstract：
Radiofrequency ablation (RFA) of cancer induces an anti-tumor immunity, which is insufficient to prevent recurrences. In mice, RFA-intratumoral immunotherapy by granulocyte-macrophage colony-stimulating factor (GM-CSF) and Bacillus Calmette-Guerin resulted in complete metastases regression. Infectious risk in human needs replacement of live vaccines. Intratumoral purified protein derivatives (PPD) have never been tested in digestive cancers, and the safety of intratumoral immunotherapy after RFA has not yet been validated in human models. We investigated the therapeutic efficacy of combined radiofrequency ablation (RFA) and intratumoral immunotherapy (ITI) using an immune-muco-adherent thermogel (IMT) in a mouse model of metastatic colorectal cancer (CRC) and the safety of this approach in a pig model. Intratumoral stability of the immunogel was assessed using magnetic resonance imaging (MRI) and bioluminescent imaging. Seventy-four CT26 tumor-bearing female BALB/c mice were treated with RFA either alone or in combination with intratumoral IMT. Regression of distant metastasis and survival were monitored for 60 days. Six pigs that received liver radiofrequency and intralesional IMT injections were followed for 15 days. Experimental gel embolisms were treated using an intravascular approach. Pertinent rheology of IMT was confirmed in tumors, by the signal stability during 3 days in MRI and 7 days in bioluminescence imaging. In mice, the abscopal effect of RFA-intratumoral immunotherapy resulted in regression of distant lesions completed at day 16 vs. a volume of 350 ± 99.3 mm3 in the RFA group at day 25 and a 10-fold survival rate at 60 days. In pigs, injection of immunogel in the liver RFA area was safe after volume adjustment without clinical, hematological, and liver biology disorder. Flow cytometry showed an early increase in CD3 TCRγδ+T cells at D7 (p < 0.05) and a late decrease in CD29+-CD8 T cells at D15 (p < 0.05), reflecting the inflammation status changes. Systemic GM-CSF release was not detectable. Experimental caval and pulmonary thermogel embolisms were treated by percutaneous catheterism and cold serum infusion. RFA-intratumoral immunotherapy as efficient and safe mini-invasive interventional oncology is able to improve ablative treatment of colorectal liver metastases.
摘要：
癌症的射频消融（RFA）诱导抗肿瘤免疫，这不足以防止复发。在老鼠身上,通过粒细胞-巨噬细胞集落刺激因子（GM-CSF）和卡介苗芽孢杆菌进行RFA-肿瘤内免疫治疗可导致转移完全消退。人类感染风险需要更换活疫苗。肿瘤内纯化蛋白衍生物（PPD）从未在消化系统癌症中进行过测试。RFA后肿瘤内免疫治疗的安全性尚未在人类模型中得到验证.我们研究了使用免疫粘膜粘附热凝胶（IMT）在转移性结直肠癌（CRC）小鼠模型中联合射频消融（RFA）和肿瘤内免疫疗法（ITI）的治疗效果，以及该方法在猪模型中的安全性。使用磁共振成像(MRI)和生物发光成像评估免疫凝胶的瘤内稳定性。用RFA单独或与肿瘤内IMT组合治疗74只携带CT26肿瘤的雌性BALB/c小鼠。监测远处转移和存活的消退60天。六只接受肝脏射频和病灶内IMT注射的猪随访15天。使用血管内方法治疗实验性凝胶栓塞。在肿瘤中证实了IMT的相关流变学，通过MRI中3天和生物发光成像中7天的信号稳定性。在老鼠身上,RFA-肿瘤内免疫治疗的切除效应导致在第16天完成的远处病变消退。RFA组在第25天的体积为350±99.3mm3，在60天的存活率为10倍。在猪中,在没有临床的情况下，容量调整后，在肝脏RFA区域注射免疫凝胶是安全的，血液学,和肝脏生物学紊乱。流式细胞术显示D7时CD3TCRγδ+T细胞早期增加(p<0.05)，D15时CD29+-CD8T细胞晚期减少(p<0.05)，反映了炎症状态的变化。未检测到系统性GM-CSF释放。通过经皮导管插入和冷血清输注治疗实验性腔和肺热凝胶栓塞。RFA-肿瘤内免疫治疗作为一种高效、安全的微创介入肿瘤学能够改善结直肠癌肝转移的消融治疗。
