基于PD-1/PD-L1 抑制剂的肺癌免疫治疗预测标志物的研究进展

[摘要] 近年来,免疫检查点抑制剂在肺癌治疗中取得突破性进展,正迅速改变着肺癌的治疗模式,也标志着免疫治疗2.0 时代的到来。新的肿瘤治疗模式对精准医学提出更高要求,对程序性死亡受体1（programmed death 1, PD-1）/程序性死亡配体1（programmed death ligand 1, PD-L1）抑制剂预后生物标志物也在不断地探索之中,主要包括以下几个方面：PD-L1 表达水平、肿瘤基因组异质性与肿瘤新抗原、T细胞特点、肿瘤微环境以及机体整体状态等。本文将针对目前PD-1/PD-L1 抑制剂在肺癌免疫治疗中的潜在生物标志物最新临床研究进展及其研究前景进行综述。     

阻断T细胞活化抑制通路治疗恶性肿瘤新进展

肿瘤免疫治疗近年来取得了较大进展,阻断T细胞活化抑制通路的抗程序性死亡受体-1（programmed death-1,PD-1）/程序性死亡配体-1（programmed death-ligand1,PD-L1）及细胞毒性T淋巴细胞抗原-4（cytotoxic T lymphocyte antigen-4,CTLA-4）等单克隆抗体（也被称为免疫检查点抑制剂）应用于临床,有些抗体已纳入特定肿瘤的一线治疗。本文就免疫检查点抑制剂（immune checkpoint inhibitors,ICPIs）的作用机制、临床研究结果、免疫相关不良事件等方面的最新进展进行综述,从而分析该领域所面临的问题及未来发展前景。      

PD-1和PD-L1在肿瘤免疫逃逸中的作用机制及临床意义

随着人们对肿瘤免疫微环境的深入研究,发现肿瘤细胞的免疫逃逸是造成肿瘤进展的关键原因,其分子机制也成为肿瘤免疫治疗研究的重点问题之一。近年研究表明程序性死亡受体-1（programmed death receptor-1,PD-1）与程序性死亡配体-1（programmed death ligand-1,PD-L1）与肿瘤发生、发展有密切联系。其中,PD-1是T细胞介导免疫反应中的重要抑制性免疫检查点,肿瘤细胞通过表达PD-L1,与肿瘤浸润淋巴细胞的PD-1结合,诱导淋巴细胞的凋亡,从而抵抗淋巴细胞的杀伤作用,最终造成肿瘤发生免疫逃逸。本文对PD-1和PD-L1在肿瘤免疫逃逸中的作用机制及在肿瘤治疗中的临床意义作一综述。     

PD-1/PD-L1治疗非小细胞肺癌的研究进展

程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand 1,PD-L1）信号通路与肿瘤免疫逃逸密切相关,针对PD-1/PD-L1通路的免疫检查点抑制剂为非小细胞肺癌（non-small cell lung cancer,NSCLC）患者提供了一种新的治疗选择,并且显示出良好的疗效和安全性。本文对PD-1/PD-L1抑制剂治疗NSCLC的临床研究进展进行综述。      

非小细胞肺癌的联合免疫治疗现状

对于晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的患者来说,化疗、放疗、靶向治疗及抗血管生成治疗虽然可以改善其预后,但经相关研究发现,NSCLC患者的5年生存率仍不尽人意。近年来以程序性死亡蛋白1（programmed cell death protein 1,PD-1）/程序性死亡蛋白配体1（programmed death-ligand 1,PD-L1）抑制剂为代表免疫检查点抑制剂的出现为晚期NSCLC患者的治疗带来了新的希望。探索免疫检查点抑制剂联合化疗、抗血管生成药物、放疗的各项治疗策略是目前肿瘤界的热门话题,本文将对NSCLC联合免疫治疗的现状进行总结与讨论。     

抗PD-1/PD-L1疗法致免疫相关不良反应机制及预测标志物的研究进展

抗程序性细胞死亡受体-1(programmed cell death protein-1,PD-1)和抗程序性死亡受体配体-1(programmed cell death ligand-1,PD-L1)是目前广泛使用的免疫检查点抑制剂,在肿瘤免疫治疗方面取得了巨大的成就,但同时也导致免疫相关不良反应(immune-related adverse events, irAEs),严重者甚至会导致患者死亡。因此,明确irAEs的发生机制,提早预测irAEs非常重要。本文由细胞、免疫系统、个体水平层面对抗PD-1/PD-L1疗法致irAEs的发生机制进行了总结,并从一般临床特征、免疫细胞因素、细胞因子相关、基因表达结果等方面汇总了irAEs的预测指标。     

免疫检查点抑制剂在恶性淋巴瘤中的应用研究进展*

免疫检查点是一类免疫抑制性分子,通过调节免疫反应的强度和广度,从而避免正常组织的损伤和破坏。近年来研究发现肿瘤细胞可通过激活免疫检查点活性,从而逃避免疫系统的监视。免疫检查点抑制剂则通过拮抗免疫检查点蛋白,促进T 细胞活化,进而产生抗肿瘤免疫效应。免疫检查点抑制剂在多种实体瘤的治疗方面已显示出良好的疗效。在淋巴瘤的治疗领域,虽然尚处于起步阶段,检查点抑制剂亦显示出良好的疗效及安全性。本文主要总结免疫检查点蛋白细胞毒性T 淋巴细胞相关抗原- 4（cytotoxic T lymphocyte associated antigen-4,CTLA- 4）、程序性死亡受体- 1（programmed death- 1,PD- 1）及其程序性死亡受体配体- 1（programmed death ligand 1,PD-L1）的生物学活性,并介绍相应抗体药物在淋巴瘤研究中的进展。      

PD-1/PD-L1抑制剂在晚期尿路上皮癌中的研究进展

摘 要：含顺铂方案的化疗是晚期尿路上皮癌的一线治疗方式,不耐受顺铂化疗的及一线标准化疗后发生疾病进展的患者可选择的有效治疗有限,平均生存期约5~10个月。程序性死亡受体1（programmed death 1,PD-1）/程序性死亡配体1（programmed death ligand 1,PD-L1）抑制剂在大型临床试验中显示出持久的抗肿瘤效应和可耐受的安全性,为改善晚期尿路上皮癌患者预后带来了希望。PD-1抑制剂Pembrolizumab是第一个获得美国食品药品管理局（Food and Drug Administration,FDA）批准的治疗晚期尿路上皮癌的一线免疫治疗药物。2种PD-1抑制剂Pembrolizumab和Nivolumab,3种PD-L1抑制剂Atezolizumab、Durvalumab和Avelumab,先后获得美国FDA批准作为含铂方案化疗进展的晚期尿路上皮癌患者的二线治疗药物。全文就PD-1/PD-L1抑制剂在晚期尿路上皮癌中的研究进展作一综述。     

PD-L2在血液系统肿瘤免疫治疗中的研究进展

随着程序性死亡受体1(programmed death receptor-1,PD-1)/程序性死亡受体配体1(programmed death-ligand 1,PD-L1)抑制剂在多种实体肿瘤临床治疗中取得广泛进展,血液系统肿瘤亦拉开了免疫疗法帷幕。然而,免疫检查点阻断疗法仍存在应答率低、药物耐药和副作用严重等挑战,需要进一步寻找新的免疫治疗靶点。B7家族中的程序性死亡受体配体2(programmed death-ligand 2,PD-L2)亦可以和PD-1结合,进而抑制免疫细胞功能。此外,PD-L2可以调控肿瘤免疫逃逸,在血液系统肿瘤中的治疗潜力仍有待研究。故本文对PD-L2的生物学特征、在血液系统肿瘤中的表达及在免疫治疗中的研究进展进行简要综述,为血液系统肿瘤通过PD-1/PD-L2通路治疗提供理论依据。     

晚期胃癌免疫检查点PD-1/PD-L1抑制剂联合治疗的研究进展

胃癌是最为常见的恶性肿瘤之一，在中国其发病率和死亡率均较高，大多数胃癌初诊即已为晚期，预后较差，目前治疗现状仍不理想。免疫逃逸是肿瘤发生发展的一主要机制，细胞程序性死亡受体-1（programmed death-1，PD-1）及细胞程序性死亡配体（programmed death-ligand 1，PD-L1）是导致免疫逃逸的重要分子，PD-1与PD-L1结合是肿瘤细胞免疫逃逸的重要发病机制之一，特异性阻断二者结合，可达到杀灭肿瘤细胞的目的。PD-1/PD-L1抑制剂可明显改善晚期胃癌患者预后，并且PD-1/PD-L1抑制剂联合化疗、靶向治疗、放疗等可进一步提高疗效。本文就PD-1/PD-L1抑制剂联合治疗在晚期胃癌中的治疗进展进行综述。      

免疫检查点抑制剂的疗效预测标志物

针对程序性死亡受体1(programmed death receptor 1,PD-1)/程序性死亡受体配体1(programmed death receptor ligand 1,PD-L1)通路的免疫检查点抑制剂（immune checkpoint inhibitors,ICI）的研究十分热门,为多种晚期肿瘤患者的治疗提供了新的希望。然而,ICI的有效率仍偏低,非目标患者对其没有应答,部分患者会出现延迟反应、假性进展等特殊应答模式,目前尚无精准的疗效预测标志物能够提前对患者的肿瘤反应及预后做出判断,使得患者在应用免疫检查点抑制剂时受到限制,本文对目前常用及部分近期研究的疗效预测标志物进行简要综述。     

晚期非小细胞肺癌化疗联合免疫治疗进展

化疗在晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）的治疗中发挥着重要的作用，但近年来免疫检查点抑制剂在晚期NSCLC的治疗中也表现出了良好的效果，因此两者联合治疗能否产生更佳的治疗效果成为了人们关注的焦点。本文综述总结了程序性死亡受体1（programmed death 1，PD-1/PD-L1）抑制剂、细胞毒性T淋巴细胞相关蛋白（cytotoxic T-lymphocyte-associat? ed protein 4，CTLA4）抑制剂等不同免疫治疗方案分别联合不同化疗方案治疗晚期NSCLC的疗效及安全性，并阐述联合治疗方案疗效增加可能的机制，同时对晚期NSCLC未来的治疗模式做出了展望。      

Immune checkpoint inhibitors in advanced non–small cell lung cancer

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first‐line and second‐line therapy settings for patients with advanced non–small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced‐stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue‐based and blood‐based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248‐61 . © 2017 American Cancer Society.     

Immunotherapy in gastrointestinal cancer: Recent results,current studies and future perspectives

The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient’s tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies.     

Clinical characteristics and responses to chemotherapy and immune checkpoint inhibitor treatment for microsatellite instability gastric cancer

During the process of DNA replication, insertions or deletions of repeat sequences easily occur in microsatellites due to DNA polymerase slippage in instances of defective mismatch repair; this phenomenon is known as microsatellite instability. Based on genetic profiling, microsatellite instability gastric cancer is regarded as a separate subtype of gastric cancer that is associated with old age, the female sex, a distal gastric location, and a lower number of lymph node metastases. According to numerous retrospective studies, microsatellite instability is a favourable predictive marker for prognosis. However, during the perioperative period, gastric cancer patients with microsatellite instability after chemotherapy often exhibit a poor and unfavourable prognosis. This result still remains controversial. The efficacy of adjuvant chemotherapy in microsatellite instability-high tumours ranges from detrimental to beneficial effects. Due to the widespread expression of immune checkpoint molecules (such as programmed death-1 and programmed death-ligand 1) in tumours with microsatellite instability, immune checkpoint inhibitors have been utilized to treat microsatellite instability gastric cancer and tremendously improve the efficacy of treatment and survival of microsatellite instability patients. In this review, we attempt to outline the definitions of microsatellites and microsatellite instability, the methods used to screen for microsatellite instability, the clinical characteristics of microsatellite instability gastric cancer, and its responses to chemotherapy and immune checkpoint inhibitor treatment. Overall, determining the status of microsatellites is essential before developing a tailored treatment strategy for patients with microsatellite instability gastric cancer.     

Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?

Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.     

Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors

Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.KEYWORDS : Cancer vaccine, immune checkpoint, immunotherapy, cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), programmed cell death ligand-1 (PD-L1)     

The promising role of nivolumab in renal cell cancers

The therapeutic efficacy of checkpoint inhibitors across numerous tumor types has resulted in approval for neoplasms such as melanoma and lung cancer. Nivolumab is a fully humanized IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells. Motzer and Colleagues published the findings of Nivolumab versus everolimus in advanced kidney cancer in the November issue of the New England Journal of Medicine. This trial showed that nivolumab resulted in better median overall survival of 25 months compared to everolimus at 19.6 months, with a hazard ratio for death at 0.73, meeting pre-specified criterion for superiority in favor of nivolumab. These findings mark the defining beneficial role of immune checkpoint inhibitor therapy in metastatic kidney cancer.     

Immune checkpoint inhibitors and elderly people: A review

Immune checkpoint inhibitors, including targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 pathways, are a new type of cancer treatment. This approach of targeting the immune system has demonstrated dramatic efficacy for several cancers, and various drugs have been approved by health authorities and are used in clinical practice. Elderly patients (≥65 years) represent most of the cancers diagnosed and deaths by age group, with an increase expected over the next decade. However, this subgroup of patients is under-represented in clinical trials. Ageing is also associated with a decrease in the effectiveness of the immune system and in alterations to it. Few specific trials have been carried out for immunotherapy in elderly people, with most patients considered to be fit. In this review, we discuss the impact of ageing and immunosenescence on immune system functions, and we assess the safety and efficacy of immune checkpoint inhibitors in elderly patients, principally from the data of pivotal clinical trials with subgroup analysis. Tolerance in elderly patients seems similar to younger people, but efficacy seems different between younger and elderly patients according to the type of cancer, some showing no difference and others less efficacy in the elderly subgroup. However, the numbers in elderly groups are small and more investigation is needed, with specific clinical trials for elderly cancer patients.     

Combination Strategies on the Basis of Immune Checkpoint Inhibitors in Non–Small-Cell Lung Cancer: Where Do We Stand?

The era of immune checkpoint inhibitors, especially programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies in the treatment of advanced non–small-cell lung cancer (NSCLC) is coming. Because of the lack of the definite biomarkers to select the optimal responders, only approximately 20% of patients with advanced NSCLC would respond to single checkpoint inhibitors-based immunotherapy. Moreover, primary or acquired resistance to conventional therapies is inevitable in most cases. Thus, combinations are pushed to move forward to be an alternative strategy and surely, it would be a future direction. Combination approaches on the basis of PD-1/PD-L1 inhibitors are currently designed to re-energize the immune system with complementary/synergetic mechanisms and could achieve durable antineoplastic effects in NSCLC. Herein, we highlight the potential combinations on the basis of PD-1/PD-L1 inhibitors in NSCLC, with other immunotherapies, chemotherapy, radiotherapy, and targeted therapy in this current review.