肝癌的免疫治疗：原则和挑战

StephenW

                                                                [color=!important]IMMUNOTHERAPY OF LIVER CANCER: PRINCIPLES AND CHALLENGES                                                                                                                                                                                       
                                                                                                                                                                        Bruno Sangro
Liver Unit, Clínica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
               
       
                                                Q. WHY SO MUCH HYPE ON THE IMMUNE THERAPIES IN THE FIELD OF LIVER CANCER?The story of drug development for hepatocellular carcinoma (HCC) has been disappointing in the past eight years with many drugs failing in phase III trials. Very recently, an increased survival was shown in patients that tolerated sorafenib but eventually had radiological progression and were next treated with regorafenib 1. But no systemic therapy is effective in the adjuvant setting after resection or percutaneous ablation, or in combination with locoregional therapies such as TACE. On the other hand, immunotherapy has revolutionized the treatment of cancer. Over the last 5 years, immune-based therapies have shown that they can prolong patient survival in a wide variety of tumors and clinical scenarios. So-called immune checkpoint inhibitors are now approved for the treatment of refractory Hodgkin’s disease; metastatic non-small cell lung cancer or locally advanced urothelial cancer resistant to chemotherapy; metastatic melanoma naive to chemotherapy; recurrent squamous cell carcinoma of the head and neck; or for the adjuvant treatment of stage III melanoma. For a good reason, the American Society of Clinical Oncology has considered immunotherapy the Advance of the Year in 2015 and 2016.
               
       
                                                Q. WHAT ARE THE IMMUNE CHECKPOINTS AND WHY ARE THEY IMPORTANT?Immune checkpoints are a specific subtype of membrane-bound molecules that provide fine-tuning of the immune response. They are expressed in different cell types involved in the immune response, including B and T cells, natural killer (NK) cells, dendritic cells, tumor associated macrophages, monocytes, and myeloid-derived suppressor cells (MDSC). The physiological function of these complexes is to prevent continuous T cell effector function upon initial stimulation and engagement of antigen-specific T cells. Thus, most of these molecules display an immunosuppressive activity that prevents uncontrolled T cell responses against infection and limit collateral tissue damage. The immune checkpoints most studied in human cancer are cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) 2. CTLA-4 is essential for the activation of helper CD4+ T cells and the priming phase of the immune response. Upon binding of its ligands, CTLA-4 decreases T cell activation following antigen presentation. CTLA-4 also plays a major role in the function of regulatory T cells (Treg), a subset of CD4+ T cells that inhibit the immune response. On the other hand, PD-1 is a key factor in the effector phase of the immune response. It is expressed by activated T and B cells and other cell types. Upon binding to its ligands (PD-L1 and PD-L2), PD-1 inhibits T cell activation and proliferation.
Monoclonal antibodies that bind these molecules and block their signaling are called immune checkpoint inhibitors. They release the brake that puts the immune response on hold and allow cytotoxic T cells to strike tumor cells. Other monoclonal antibodies may target different checkpoint molecules that provide positive signals for T cell or NK cell activation and proliferation, but they are at much earlier phases of clinical development.
               
       
                                                Q. WHAT IS THE EXPERIENCE WITH THE USE OF CHECKPOINT INHIBITORS IN HCC?Tremelimumab (a CTLA-4 blocking monoclonal antibody) was first evaluated in a small phase II trial that targeted patients with HCC and chronic HCV infection 3. Twenty-one patients with advanced disease were enrolled, including a significant proportion (42.9%) of patients in Child-Pugh stage B. Despite receiving a suboptimal dose of tremelimumab, a notable disease control rate of 76.4% was observed among 17 evaluable patients, including 3 partial responses and 4 prolonged (>6 months) stabilizations. Tremelimumab was well tolerated, with few patients experiencing grade 3 disabling adverse events (AE), even in the presence of liver dysfunction. In a second small pilot trial, incomplete tumor ablation using percutaneous radiofrequency (RFA) or transarterial chemoembolization (TACE) was combined in an attempt to enhance the effects of tremelimumab by inducing immunogenic tumor cell death 4. In this study, liver function was preserved in the most patients, all etiologies were included and the dose of tremelimumab was the standard. Nineteen patients were evaluable for response because they had measurable lesions that were not targeted by RFA or TACE. A disease control rate of 89% was reported, including 5 partial responses (26%) and 5 prolonged stabilizations. The median overall survival of 12.3 months compares well with placebo-treated patients in the second-line setting.
These encouraging signs of antitumor activity and good safety profile provided a strong reason to test PD-1 inhibitors [17]. Nivolumab (a PD-1 blocking monoclonal antibody) has been tested as first or second-line treatment in patients with advanced HCC across different etiologies (HCV infection, HBV infection, non-viral cirrhosis) 5. A dose-escalation cohort of 48 patients was followed by an expansion cohort of 214 patients treated with 3 mg/kg. Most patients had extrahepatic metastases (68%), and had received prior systemic therapy (76%), mainly Sorafenib. Treatment was by and large well tolerated with only 3% of patients discontinuing nivolumab due to treatment-related AE. Convincing signs of efficacy consisted in objective tumor responses in 15-20% of patients, which lasted for a median of 17 months. An additional 45% of patients had stable disease that was frequently durable too. These signs of efficacy were consistent with the most recently reported median overall survival of 28.6 months in the population naive to sorafenib, and 15.6 months in the population exposed to sorafenib (90% progressors) 6. This median survival compares well with any other phase 2 or 3 clinical trial of targeted agents including regorafenib, the first agent shown to prolong survival following sorafenib in a selected group of sorafenib-tolerant patients.
               
       
                                                Q. WHAT ARE THE MAIN CHALLENGES FOR IMMUNOTHERAPY OF HCC?Encouraging as they are, the results of the reported trials pose a number of challenges. First, checkpoint inhibitors should be tested in the first line setting. Indeed, a large phase III trial is comparing nivolumab and sorafenib as first line therapy in advanced HCC and the results will likely be reported in 2018. Second, their activity has to be tested in the intermediate stage (in combination with intraarterial therapies that are the standard of care) and in the early stage (as adjuvant therapy after resection or ablation). Third, 30% to 40% of patients do not respond to these agents. The mechanisms of primary resistance are largely unknown 7 but combination strategies may work in these patients as we have learned in melanoma. Indeed, several combinations of checkpoint inhibitors with other therapies are being tested. They may be based on the potential additive effect of a therapy with a proven treatment benefit (TACE or sorafenib) or is being investigated (ramucirumab, cabozantinib), but they can also be based on exploiting synergistic effects (radioembolization, oncolytic virotherapy) or avoiding primary resistance (anti-CTLA-4 plus anti-PD1/PD-L1, tumor vaccines). Finally, evaluation of tumor response and selection of the best candidates based on easily accessible biomarkers remain a true challenge.
               
       

StephenW

肝癌的免疫治疗：原则和挑战

布鲁诺桑格罗
肝脏单位，Clínica纳瓦拉大学IDISNA和CIBEREHD，潘普洛纳，西班牙。
问：为什么对肝癌领域的免疫疗法产生过多的反应？

在过去的八年中，许多药物在III期临床试验中失败，肝细胞癌（HCC）药物开发的故事令人失望。最近，耐受索拉非尼但最终有放射学进展的患者中存活率增加，接下来用瑞格非尼1进行治疗。但是，在切除或经皮消融后的辅助设置中，或者与局部治疗例如TACE。另一方面，免疫疗法已经彻底改变了癌症的治疗。在过去的5年中，基于免疫的治疗已经表明它们可以延长患者在各种肿瘤和临床情况下的存活率。所谓的免疫检查点抑制剂现在被批准用于治疗难治性何杰金氏病;转移性非小细胞肺癌或对化学疗法耐受的局部晚期尿路上皮癌;对化疗无效的转移性黑素瘤;复发性头颈部鳞状细胞癌;或用于III期黑素瘤的辅助治疗。有一个很好的理由，美国临床肿瘤协会已经在2015年和2016年考虑了免疫疗法的年度进展。
问：什么是免疫检查点，它们为什么重要？

它们在涉及免疫反应的不同细胞类型中表达，包括B和T细胞，自然杀伤（NK）细胞，树突细胞，肿瘤相关巨噬细胞，单核细胞和骨髓来源的抑制细胞（MDSC）。这些复合物的生理功能是在初始刺激和接触抗原特异性T细胞时阻止连续的T细胞效应子功能。因此，大多数这些分子显示出。在人类癌症中研究最多的免疫检查点是细胞毒性T淋巴细胞蛋白4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）2。CTLA-4对于活化辅助性CD4 + T细胞和免疫应答的启动阶段。在其配体结合后，CTLA-4减少T细胞活化褶皱，降低抗原呈递。 CTLA-4在调节性T细胞（Treg）的功能中也起主要作用，Treg是抑制免疫应答的CD4 + T细胞亚群。另一方面，PD-1是免疫应答效应阶段的关键因素。它由活化的T和B细胞和其他细胞类型表达。在与其配体（PD-L1和PD-L2）结合后，PD-1抑制T细胞活化和增殖。

结合这些分子并阻断其信号传导的单克隆抗体在保持时进行免疫检查并允许细胞毒性T细胞敲击肿瘤细胞。他们释放刹车，使免疫反应持续，并允许细胞毒性T细胞击中肿瘤细胞。 T细胞或NK细胞的活化和增殖，但是它们处于临床开发的较早阶段。
问：在HCC中使用检查点抑制剂有什么经验？

Tremelimumab（一种CTLA-4阻断性单克隆抗体）首先在针对HCC和慢性HCV感染患者的小型II期临床试验中进行评估.3名患有晚期疾病的患者入组，其中包括显着比例（42.9％）的患者尽管接受次优剂量的tremelimumab，在17个可评估的患者中观察到显着的疾病控制率76.4％，包括3个部分响应和4个延长的（> 6个月）稳定。 Tremelimumab耐受性良好，少数患者出现3级禁用不良事件（AE），即使存在肝功能障碍。在第二个小型试点试验中，使用经皮射频（RFA）或经动脉化疗栓塞（TACE）的不完全肿瘤消融试图通过诱导免疫原性肿瘤细胞死亡4来增强tremelimumab的作用。在该研究中，肝功能被保存在包括所有病因的大多数病人，以及由于具有不被RFA或TACE靶向的可测量损伤而可评价的19名患者。据报道，疾病控制率为89％，其中包括5个部分反应（26％）和5个长期稳定。12.3个月的中位总生存期与安慰剂治疗的患者在二线环境中相当。
这些令人鼓舞的抗肿瘤活性和良好的安全性提供了一个强有力的理由来测试PD-1抑制剂[17]。 Nivolumab（一种阻断PD-1的单克隆抗体）已经作为不同病因（晚期肝细胞癌，HBV感染，非病毒性肝硬化）的晚期HCC患者的一线或二线治疗试验.5个剂量递增队列的48名患者随后是214名接受3mg / kg治疗的患者的扩充队列。大多数患者有肝外转移（68％），曾接受过全身治疗（76％），主要是索拉非尼。只有3％的患者由于治疗相关性AE而停用nivolumab，因此治疗大体上可以耐受。令人信服的疗效标志包括客观肿瘤反应的15-20％的患者，持续了17个月的中位数。另有45％的患者病情稳定，也经常耐用。这些疗效的迹象与索拉非尼最初报告的中位总生存期28.6个月相一致，而索拉非尼组中的总生存期为15.6个月（90％的进展者）6.这个中位生存期与任何其他的2期或3项临床试验，包括瑞格非尼（regorafenib），第一种药物显示可延长索拉非尼在选定的索拉非尼耐药患者组中的存活率。
问：HCC免疫治疗的主要挑战是什么？

尽管鼓舞人心，但所报告的审判结果带来了诸多挑战。首先，检查点抑制剂应在第一线设置进行检测。事实上，一项大型Ⅲ期临床试验正在比较nivolumab和索拉非尼作为晚期HCC的一线治疗方案，结果可能会在2018年报告。其次，它们的活性必须在中期阶段进行测试（联合动脉内治疗标准护理）和早期（作为切除或消融后的辅助治疗）。第三，30％到40％的患者对这些药物没有反应。原发性耐药的机制在很大程度上是未知的7，但是在黑素瘤中我们已经了解到，这些患者可以使用组合策略。事实上，检测点抑制剂与其他疗法的几种组合正在测试中。它们可能基于已证实的治疗益处（TACE或索拉非尼）或正在研究（雷莫芦单抗，cabozantinib）的治疗的潜在累加效应，但是它们也可基于利用协同效应（放射栓塞，溶瘤病毒疗法）或避免原发性耐药（抗CTLA-4加抗PD1 / PD-L1，肿瘤疫苗）。最后，基于容易获得的生物标志物评估肿瘤反应和选择最佳候选者仍是真正的挑战。

antiHBVren

每一种新的治疗方案面世，伴随着新难关的攻破，总有着不同的副作用