肝细胞癌免疫治疗临床研究进展

原发性肝癌是中国癌症第2大死因,其中肝细胞癌占80%～90%,各种治疗方法疗效欠佳,总体生存期较短。以免疫检查点抑制剂为核心的免疫治疗在肝细胞癌临床研究中表现出较好疗效,并获得相关指南支持。对于晚期肝细胞癌,免疫检查点抑制剂可单药或双药联用,可联合血管内皮生长因子抑制剂或酪氨酸激酶抑制剂。对早期和中期肝癌,免疫检查点抑制剂可联合局部治疗。此外,免疫细胞治疗也逐渐进入临床试验阶段。就肝细胞癌免疫治疗临床研究的最新进展进行综述,以期为临床应用和深入研究提供参考。     

介入热灌注化疗中晚期肝癌患者免疫功能的影响

目的探讨介入热灌注化疗中晚期肝癌患者免疫功能的影响。方法采用流式细胞仪检测60例原发性肝癌患者介入热灌注热化疗前后T细胞亚群细胞的变化,并与40例常规介入化疗栓塞组进行比较。结果两组CD3^＋、CD4^＋、CD4^＋／CD8^＋升高,CD8^＋下降（P〈0．05）;热疗组CD3^＋、CD4^＋、CD4^＋／CD8^＋明显高于非热疗组,差异有统计学意义（P〈0．05）。结论介入灌注化疗可以提高中晚期肝癌患者的细胞免疫功能。     

Emerging tyrosine kinase inhibitors for the treatment of hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is the fifth most diagnosed cancer in the world and the third leading cause of death. Unfortunately, when diagnosed two thirds of patients have an advanced disease for which only palliative treatment can be proposed and most likely systemic therapy.

Areas covered: As of today only one systemic therapy is validated in the treatment of advanced HCC, a tyrosine kinase inhibitor (TKI): Sorafenib. Treatment options are therefore lacking. With the advent of Sorafenib other TKIs have been studied with some disappointing results. Many explanations can be found to the failure of these tested TKIs such as the underlying cirrhosis leading to rapidly serious adverse events, or trial design imperfections.

Expert opinion: Taking into account these failures, new trials with more appropriate designs have led to recent success with multi-target TKIs (Regorafenib and Lenvatinib). This multi-target approach allows to overcome the molecular heterogeneity of advanced HCC which is associated with multiple simultaneously dysregulated signaling pathways. On the contrary, another lead is to study target a specific TKI such as c-MET inhibitors or TGFβR inhibitors in HCC sub-populations with promising results in early phase trials. These results will have to be validated in the ongoing phase III trials.     

Sorafenib for the treatment of hepatocellular carcinoma across geographic regions

Sorafenib is an oral multikinase inhibitor targeting Raf, VEGF receptor, PDGF receptor, c-kit, Flt-3 and rearranged during transfection (RET). Two randomized, placebo-controlled trials for Western and Asian patients, respectively, demonstrated that sorafenib significantly prolongs overall survival and time to progression in patients with advanced hepatocellular carcinoma (HCC). These have become the reference treatment for future clinical trials of advanced HCC. Sorafenib is well tolerated in patients with Child–Pugh liver function class A, but limited data are available in Child–Pugh class B and C patients. Clinical trials are ongoing to test the efficacy of sorafenib-based combination therapy and sorafenib adjuvant therapy for HCC.     

Tivantinib for the treatment of hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with a poor prognosis due to late diagnosis in the majority of cases. Physicians are frequently confronted with patients who are not eligible for curative or locoregional treatments any more. In this scenario, the multi-tyrosine kinase inhibitor sorafenib remains the only systemic first-line treatment option providing modest survival benefit compared to placebo with significant but for most patients acceptable adverse effects.

Areas covered: Tivantinib was the first antiproliferative agent to be been applied in a phase III trial based on receptor overexpression analyses after disease progression on sorafenib. While phase I and II trials with tivantinib in second line showed encouraging results, a recent press release announced that the METIV-HCC phase III study of tivantinib in HCC did not meet its primary endpoint of improving overall survival.

Expert commentary: Evidence for antiangiogenetic therapy inducing tumor hypoxia leading to overexpression of proliferative genes, including cMET, underlines the potential of tivantinib as second-line treatment. However, as the mechanism of action of tivantinib through cMET inhibition has recently been questioned by several groups, identification of alternative proliferative markers or targets is mandatory.     

Pharmacokinetics,pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma

Introduction: Nivolumab is a recombinant, humanized monoclonal antibody that binds PD-1. The binding of PD-1 with PD-L1, expressed on antigen-presenting cells and tumor cells, suppresses the ability of T-lymphocytes to recognize and destroy tumor cells. Nivolumab reverts this inhibitory signal and has led to a significant prolongation of overall survival in patients with metastatic renal cell carcinoma (RCC).

Areas covered: The rationale for immunotherapy in metastatic RCC, key immune checkpoint pathways, nivolumab pharmacodynamics, results from the main clinical trials, and predictors of response are discussed.

Expert opinion: Nivolumab demonstrated a statistically significant advantage over everolimus in overall survival in metastatic RCC patients after first-line antiangiogenic therapy. Nevertheless, a number of issues remain to be resolved regarding the use of this drug in RCC. It is now imperative to identify which patients can benefit most from immunotherapy and studies are ongoing to define its role in other settings and/or in combinations with antiCTLA4 or antiangiogenic drugs.     

Anti-GPC3 antibody-modified sorafenib-loaded nanoparticles significantly inhibited HepG2 hepatocellular carcinoma

Sorafenib (SFB) has improved the treatment of hepatocellular carcinoma (HCC) and has fewer severe side effects than other agents used for that purpose. However, due to a lack of tumor-specific targeting, the concentration of the drug in tumor tissue cannot be permanently maintained at a level that inhibits tumor growth. To overcome this problem, we developed a novel SFB-loaded polymer nanoparticle (NP). The NP (a TPGS-b-PCL copolymer that was synthesized from ε-caprolactone and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via ring-opening polymerization) contains Pluronic P123 and SFB, and its surface is modified with anti-GPC3 antibody to produce the polymer nanoparticle (NP-SFB-Ab). The Ab-conjugated NPs had higher cellular uptake by HepG2 cells than did non-antibody-conjugated SPD-containing nanoparticles (NP-SFB). The NP-SFB-Ab also displayed better stability characteristics, released higher levels of SFB into cell culture medium, and was more cytotoxic to tumor cells than was non-targeted NP-SFB and free SFB. The NP-SFB-Ab downregulated expression of the anti-apoptosis molecule MCL-1, which led to polymerization of Bax and Bak in mitochondrial cytosol. The NP-SFB-AB also promoted the mitochondrial release of cytochrome C, resulting in cellular apoptosis. Moreover, the NP-SFB-Ab significantly inhibited the growth of HepG2 xenograft tumors in nude mice without producing obvious side effects. These findings suggest that NP-SFB-Ab is a promising new method for achieving targeted therapy of HCC.     

重复射频消融治疗原发性肝癌的临床疗效观察

目的评价经皮肝穿刺重复射频消融治疗原发性肝癌的临床疗效。方法将88例原发性肝癌患者按单次射频消融及重复射频消融的方法分为2组,观察每组肿瘤完全消融率、肿瘤复发率及不良反应的发生情况。结果 2组均未发生出血、胆漏等严重的不良反应,单次射频消融组肿瘤的完全消融率为62.5%,重复射频消融组为87.5%,2组间比较差异有统计学意义(P<0.05);单次射频消融组肿瘤的复发率为20.0%,重复射频消融组为4.2%,2组间比较差异有统计学意义(P<0.05)。结论重复射频消融可有效提高原发性肝癌的临床治疗效果。     

对甲苯磺酸索拉非尼的合成

吡啶甲酸经氯化、酰胺化、亲核取代得中间体4-（4-氨基苯氧基）-2-（甲基氨甲酰基）吡啶,与4-氯-3-（三氟甲基）苯异氰酸酯缩合、再成盐得对甲苯磺酸索拉非尼,总收率为64%。     

Enhanced sensitivity of hepatocellular carcinoma cells to chemotherapy with a Smac-armed oncolytic adenovirus

Aim： The aim of the present study was to further improve the therapeutic effects for human hepatocellular carcinoma （HCC） and reduce the damage in normal cells using a novel chemo-gene-virotherapeutic strategy. Methods： An oncolytic adenoviral vector （ZD55） similar to the typical oncolytic adenovirus ONYX-015, with a deletion of E1B-55K gene, was employed to express the second mitochon- dria-derived activator of caspases （Smac） protein by constructing a recombinant virus ZD55-Smac. The enhanced cytotoxicity of the combined treatment of ZD55- Smac with cisplatin or 5-fluorouracil （5-FU） was evaluated in several HCC cell lines. Moreover, the negative effects on normal cells have been tested in human normal liver cell lines L-02 and QSG-7701 cell lines by 3-（4,5-dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide assay and apoptotic cell staining. Results： According to our observation, ZD55-Smac is superior to ONYX-015 in sensitizing chemotherapy, ZD55-Smac used in conjunction with chemotherapy was found to exhibit obviously enhanced cytotoxicity in HCC cells, yet significantly abolished the negative toxicity in normal cells by utilizing the tumor selective replication vector and reducing the dosage. Conclusion： This chemo-gene-virotherapeutic （cisplatin or 5-FU＋ZD55-Smac） strategy is superior to the conventional chemo- gene or chemo-viro approach.     

拉米夫定联合肝动脉化疗对乙肝后肝癌病人的临床治疗观察

目的：观察21例经肝动脉化疗联合拉米夫定治疗的乙型肝炎病毒（HBV）相关性肝癌病人肝功能变化。方法：对经肝动脉化疗的HBV相关性肝癌病人,根据是否口服拉米夫定分为两组,治疗组：12例经肝动脉化疗和口服拉米夫定治疗,对照组：9例仅经肝动脉化疗,未口服拉米夫定治疗。结果：治疗组HBV—DNA水平明显降低,拉米夫定没有引发YMDD及核心启动子区突变。虽然治疗组ALT、TSB、PT前后没有改变,但是对照组的ALT、TSB却出现升高、肼延长。结论：拉米夫定治疗可降低HBV—DNA水平,并能防治乙型肝炎病毒阳性的肝癌病人在化疗过程中肝损害的加重。     

手术治疗肝癌合并门静脉癌栓的效果

目的探讨原发性肝癌(HCC)合并门静脉癌栓(PVTT)的外科治疗效果。方法 63例肝癌合并门静脉癌栓患者中,17例(A组)行肝癌切除加门静脉癌栓取栓术,术后再加大网膜静脉双插管灌注化疗;其余46例(B组)行非手术治疗,包括射频治疗24例、无水酒精注射14例、介入治疗8例。结果 A组术后1、2和3年的生存率分别为65.2%、41.2%、23.5%,明显高于B组的45.7%、28.3%和0%(P<0.05)。结论与非手术治疗比较,手术治疗能相对延长肝癌合并门静脉癌栓患者的生存时间,方便术后使用大网膜静脉插管灌注化疗。     

Effect of sorafenib on the energy metabolism of hepatocellular carcinoma cells

Recent data demonstrated that sorafenib impaired the oxidative phosphorylation of a rat myogenic cell line and suggested that this biochemical lesion can contribute to the cardiac toxicity caused by the drug. With the experiments reported here, we verified whether sorafenib inhibits oxidative phosphorylation also in cells from human hepatocellular carcinomas (HCCs), which are treated with this drug. By using the HCC cell lines PLC/PRF/5 and SNU-449 we studied the effects of the drug on ATP cellular levels, oxygen consumption and aerobic glycolysis, a metabolic pathway generally used by neoplastic cells to meet their energy demand. The effect of sorafenib on ATP cellular levels was also studied in cells grown in a glucose-free medium, which only derive their energy from oxidative phosphorylation. We found that at clinically relevant concentrations sorafenib hindered oxidative phosphorylation, whereas at the same time stimulated aerobic glycolysis in glucose-grown cells, thus attenuating the cellular ATP depletion. These results support the impairment of oxidative phosphorylation as a mechanism contributing to the antineoplastic activity of sorafenib in the treatment of HCCs.     

索拉非尼相关手足皮肤反应的研究进展

甲苯磺酸索拉非尼是一种口服多激酶抑制剂,自2005年12月获得FDA批准以来,已成为无法切除的肝细胞癌的一线治疗药物。索拉非尼已被证实具有较好的安全性,但是手足皮肤反应作为其最常见的不良反应,虽然不危及生命,但可导致药物剂量改变或中断用药,从而限制抗肿瘤作用。本文就索拉非尼引起手足皮肤反应的临床特征、发病机制、预防及患者管理策略等进行综述,以期为该不良反应的临床管理和防治提供参考,提高患者用药依从性和抗肿瘤效果。     

Advancing pharmacological treatment options for advanced gastric cancer

Introduction: Gastric cancer is the third most common cause of cancer-related deaths worldwide. Improvement of conventional chemotherapy has been modest in the past decades.

Areas covered: We review recent important studies of metastatic or recurrent gastric cancer. For human epidermal growth factor receptors 2 (HER2) negative cancer, standard treatments are combinations of fluoropyrimidine and platinum with or without epirubicin or docetaxel in first-line therapy. Controversy exists regarding the use of triplet chemotherapies due to their toxicity. For HER2 positive cancer, standard treatments are combinations of fluoropyrimidine and cisplatin with trastuzumab. As second- or third-line treatment, taxanes or irinotecan prolonged survival compared with best supportive care alone, but the extension of overall survival was only 1 – 2 months. A recent study demonstrated that ramucirumab plus paclitaxel improved survival as a second-line therapy.

Expert opinion: Most trials have failed to demonstrate a benefit of targeted agents. It is important to identify predictive biomarkers to enrich an appropriate patient population for targeted agents such as HER2 status for trastuzumab.     

Economic evaluation of sorafenib in the treatment of hepatocellular carcinoma in Canada

ABSTRACT

Background: A randomized phase III trial of sorafenib vs. placebo in hepatocellular carcinoma (HCC) demonstrated that sorafenib significantly prolonged overall survival (OS) compared to placebo.

Research design and methods: A Markov model was developed to evaluate the cost-effectiveness of sorafenib vs. best supportive care (BSC) in HCC from the perspective of the Canadian provincial Ministry of Health. The model followed survival and time to progression (TTP) in monthly cycles based on the extrapolation of patient level trial data. Health effects were expressed as life-years gained (LYG). Resource use included drugs, physician visits, laboratory tests, scans, and hospitalizations. Unit costs were gathered from public sources and were expressed in 2007 Canadian Dollars. Costs and effects were evaluated over a lifetime and discounted at 5%. Results were presented as mean ± standard deviation. Deterministic and probabilistic sensitivity analyses were conducted.

Results: LYG was longer for sorafenib (1.52 ± 0.16 vs. 1.03 ± 0.09 LYG/patient for sorafenib and BSC, respectively). The lifetime total costs were $47 511 ± 3 656 for sorafenib and $10 376 ± 1 649 for BSC, resulting in an incremental cost–effectiveness ratio (ICER) of $75 821/LYG, and deterministic ICER of $75 759/LYG. The results were most sensitive to OS, TTP and BSC costs after progression. Sensitivity analyses results showed that the model was robust.

Conclusions: The economic evaluation indicates that sorafenib is cost-effective as compared to BSC in HCC. Limitations include multiple data sources, use of expert opinion for resource use, and the lack of utility data.     

CIK细胞治疗中晚期肝细胞肝癌的临床研究

目的评估细胞因子诱导的杀伤细胞(C IK细胞)过继免疫疗法治疗中晚期肝细胞肝癌的临床疗效。方法144例中晚期肝细胞肝癌患者,随机分为4组:单纯肝动脉插管栓塞化疗即单介入(TACE)组30例,肝动脉插管栓塞化疗联合经皮肝瘤体内注入无水乙醇即双介入(TACE PE I)组62例,C IK细胞回输联合单介入组16例,C IK细胞回输联合双介入组36例,进行治疗前后的疗效比较。结果C IK 双介入组、双介入组、C IK 单介入组、单介入组近期有效率分别为91.7%、75.8%、75.0%、43.3%;C IK联合介入组的AFP下降、细胞免疫功能、卡氏评分均优于双介入组和单介入组,生存期也显著延长。结论C IK细胞联合介入治疗中晚期肝细胞肝癌增强了抗癌效果,改善了患者的生存质量,延长了患者的生存期。