免疫检查点抑制剂与抗血管生成药物合用治疗肿瘤的研究进展

免疫检查点抑制剂(immune checkpoint inhibitor,ICI)通过阻断免疫负调节信号激活机体的抗肿瘤免疫应答,临床试验表明,ICI仅对部分晚期癌症患者有效。而通过阻断肿瘤血管生成常用的抗血管生成药物尽管可以抑制肿瘤的生长,对患者的生存期却未体现出改善,且存在耐药等应用局限。肿瘤免疫反应与血管生成密切相关,同时,肿瘤血管生成高度依赖于免疫抑制微环境。近来一些研究表明,ICI联合血管生成抑制剂不但可以减轻其治疗耐药性,且疗效优于任何单一疗法。联合疗法加强血管正常化和免疫重编程之间的正反馈循环,调节肿瘤免疫微环境以诱导机体持久的抗肿瘤免疫反应。该文对ICI联合抗血管生成疗法的最新进展展开论述,以期为后续研究提供新的思路与借鉴。     

免疫检查点抑制剂联合抗血管生成药物在非小细胞肺癌肝转移中的应用现状

肝脏是非小细胞肺癌（NSCLC）常见的转移部位之一。肝转移是困扰NSCLC治疗和预后的关键问题,因此须为肝转移人群寻求治疗策略。近年来免疫检查点抑制剂在NSCLC中已实现重大突破,然而有文献表明肝转移患者对免疫检查点抑制剂的反应较差,这可能与肝脏独特的微环境有关。鉴于免疫检查点抑制剂（ICI）和抗血管生成药物均靶向肿瘤微环境,越来越多的证据证实ICI联合抗血管生成药物可以发挥协同抗肿瘤作用。然而,这种联合疗法对肝转移患者的疗效尚不清楚。本文探讨了肝脏独特的微环境及联合疗法潜在协同抗肿瘤机制和在肝转移人群中临床研究进展,以期为肝转移患者治疗策略提供线索。     

活性氧对肿瘤免疫检查点的调控作用及机制研究进展

免疫检查点(immune checkpoints, ICs)是一类在免疫细胞上表达的免疫抑制性分子,能调节免疫激活程度。免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)可阻断免疫检查点与其配体结合,抑制肿瘤免疫逃逸作用,提高免疫系统对肿瘤细胞的杀伤作用,逐渐成为肿瘤治疗的一种常规策略。然而,响应率低与耐药性的产生严重影响了免疫检查点抑制剂的临床疗效。活性氧(reactive oxygen species, ROS)是一类性质活泼的氧的电子还原产物,也是细胞代谢的天然副产物,可作为细胞间信号传递的调节分子。肿瘤微环境(tumor microenvironment,TME)常处于氧化应激(oxidative stress, OS)状态,即氧化系统与抗氧化系统之间的失衡状态。存在于TME中的ROS可通过调节肿瘤免疫检查点的表达及活性,影响免疫检查点与其配体之间的相互作用,进而影响免疫细胞的抗肿瘤作用。越来越多的研究表明, ROS可通过多种途径调控肿瘤免疫检查点。因此,选择合适的ROS调节剂与免疫检查点抑制剂联合用药,可为肿瘤免疫发挥协同增效作用。本文就...     

“血管-免疫交联”策略在肿瘤治疗中的研究进展

恶性肿瘤是目前威胁人类健康安全的重要原因之一,抗血管生成药物和免疫检查点抑制剂的应用为肿瘤治疗带来了希望,然而肿瘤血管与免疫微环境之间相互交错的复杂关系导致其疗效不如人意。散乱的肿瘤血管阻碍CD8⁺T细胞进入肿瘤微环境,而且肿瘤血管生成的关键驱动力VEGF干扰树突状细胞的成熟,从而抑制T细胞的启动,VEGF还诱导CD8⁺T细胞的耗竭。同时,多种先天免疫细胞和获得性免疫细胞分泌促血管生成因子,加速失控的血管生成,促进血管不成熟。因此,靶向肿瘤血管和免疫是加强肿瘤免疫治疗的一种有潜力的策略。近年来,大量研究发现运用血管与免疫相互干预的策略来进行联合抗肿瘤免疫治疗取得了很好的效果。该综述对免疫和血管交联肿瘤微环境进行总结与讨论,综述了近几年内运用血管-免疫相互干预策略治疗肿瘤的研究进展,为进一步提高肿瘤免疫治疗的疗效提供参考。     

肿瘤血管生成抑制剂的治疗局限和策略

血管生成抑制剂通过抑制肿瘤血管生成,使肿瘤细胞处在恶劣的生长环境中,而有效阻断肿瘤的发展进程。但在临床应用中,抗血管生成的药物却表现出治疗效果短暂、不良反应较多、适用肿瘤类型少等局限。这些问题制约着药物开发与应用,限制肿瘤治疗的研究进展。诸多文献研究显示,肿瘤细胞可以通过多种机制和途径逃脱血管生成抑制剂的治疗,使血管生成抑制剂"失效"。该文着重分析治疗失效的原因和机制,拟提出对应的解决策略,以改善目前抗血管生成药物疗效,为抗血管生成新药研发及临床用药提供参考。     

CIK细胞联合抗肿瘤药物在原发性肝细胞癌治疗中的进展

原发性肝细胞癌是世界范围内的一种常见疾病,经导管动脉化疗栓塞术(TACE)及手术切除是原发性肝细胞癌的首选治疗方法.但是,手术切除肿瘤复发率高、并发症较多等,栓塞治疗后局部组织缺血、缺氧,促进了血管内皮生长因子的活化,进而促进新生血管形成,导致肿瘤复发,降低疗效,抗肿瘤血管生成治疗能弥补其缺点.CIK细胞可直接杀伤肿瘤细胞,并可增强机体的免疫功能,而成为治疗肿瘤的重要辅助疗法.因此,CIK细胞联合抗血管生成药物成为近年非手术治疗肝细胞癌的热点.     

PD-1/PD-L1抑制剂治疗晚期肝细胞癌的研究进展

随着肿瘤免疫治疗的不断应用,免疫检查点抑制剂(ICI)治疗肿瘤的相关临床研究开展广泛.多项研究表明,以程序性死亡受体/配体1(PD-1/PD-L1)抑制剂为代表的ICI在肝细胞癌治疗中取得了较好的疗效并改善了患者生存期;除单药治疗外,PD-1/PD-L1抑制剂还能与化疗、靶向药物及其他ICI联合治疗.但免疫治疗相关不良...     

PD-1抑制剂治疗左肾透明细胞癌致重症心肌炎1例

<正>免疫检查点抑制剂(ICIs)是继手术、放化疗、靶向治疗后,临床应用最广泛的肿瘤免疫治疗方式,ICIs是通过抗体抑制免疫检查点的活性,恢复并提高T细胞的功能,调动机体免疫系统,增强抗肿瘤免疫能力,从而起到抑制和杀伤肿瘤的作用^[1]。目前上市的ICIs有两种：程序性细胞死亡蛋白1(PD-1)及配体PD-L1抑制剂,细胞毒性T淋巴细胞相关抗原 4(CTLA4)抑制剂。在临床应用较多的PD-1抑制剂包括：特瑞普利单抗、卡瑞利珠单抗、     

内皮抑素概论及抗肺癌作用

肿瘤的生长转移与肿瘤血管生成密切相关,抗血管生成是治疗肿瘤的新策略.内皮抑素是特异性的血管内皮细胞生长抑制因子,能显著抑制肿瘤血管增生并诱导肿瘤细胞凋亡.内皮抑素的抗血管生成治疗和血管靶向基因治疗,为治疗肺癌提供了广阔前景 .     

抗菌药物对PD-1/PD-L1抗体免疫治疗有效性影响的研究

目的 为恶性肿瘤患者在使用免疫检查点抑制剂(Immune checkpoint inhibitors,ICI)期间,合理选用临床抗菌药物方案及改善ICI治疗临床结局策略上提供参考.方法 检索CNKI、万方、PubMed、Web of Science等数据库的国内外文献,对使用免疫检查点抑制剂期间使用抗菌药物的临床研究,...     

Immune checkpoint inhibitors: a patent review (2010-2015)

Introduction: Immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies, are revolutionizing therapeutic concepts in the treatment of cancer. Said class of drugs will represent a multi-billion dollar market over the coming decade. Many companies have therefore developed important patent activities in the field.

Areas covered: The present review gives an overview of the patent literature during the period 2010-2015 in the field of immune checkpoint inhibitors. In particular, the review presents a selection of international patent applications related to inhibitors of PD-1/PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39.

Expert opinion: Immune checkpoint inhibitors are now widely accepted as a key component of the therapeutic strategies in cancer. This fervent activity creates a maze of third-party patents that pose considerable risks for both newcomers and established companies. We can thus anticipate that the number of patent conflicts and disputes will increase in the near future. Treatments will involve combination therapy comprising at least one immune checkpoint inhibitor and companies will multiply patent filings in this field. Finally, we can expect that patents related to biomarkers that will render a patient eligible to a treatment with an immune checkpoint inhibitor will have tremendous commercial value.     

Abscopal effect in radioimmunotherapy

Abscopal effect is an interesting phenomenon in radiobiology that causes activation of immune system against cancer cells. Traditionally, this phenomenon was known as a suppressor of non-irradiated tumors or metastasis. However, it can be used as a stimulator of the immune system against primary tumor during radiotherapy. Immunotherapy, a novel tumor therapy modality, also triggers immune system against cancer. To date, some immunotherapy types have been developed. However, immune checkpoint blockade is a more common modality and some drugs have been approved by the FDA. Studies have shown that radiotherapy or immunotherapy administered alone have low efficiency for tumor control. However, their combination has a more potent anti-tumor immunity. For this aim, it is important to induce abscopal effect in primary tumors, and also use appropriate drugs to target the mechanisms involved in the exhaustion of cytotoxic CD8+T lymphocytes (CTLs) and natural killer (NK) cells. Among the different radiotherapy techniques, stereotactic body radiation therapy (SBRT) with some few fractionations is the best choice for inducing abscopal effect. On the other hand, programmed cell death 1 (PD-1) is known as one of the best targets for triggering anti-tumor immunity. This combination is known as the best choice among various strategies for radioimmunotherapy. However, there is the need for other strategies to improve the duration of immune system’s activity within tumor microenvironment (TME). In this review, we explain the cellular and molecular mechanisms behind abscopal effect by radiotherapy and evaluate the molecular targets which induce potent anti-tumor immunity.     

Novel immunotherapy in the treatment of advanced non-small cell lung cancer

Introduction: Lung cancers remain the principal cause of death cancer-related worldwide with a poor survival rate at five years from diagnosis. In patients with NSCLC harboring specific genetic alterations the anti EGFR TKIs and the ALK TKIs have improved the response rate and the quality of life compared to standard platinum-based chemotherapy. New approaches possibly applicable at the major of patients are needed.

Areas covered: The discovery that the immune system plays a fundamental role in the fight against cancer. The cancer cells use mechanisms able to avoid the immune control has led to the development of drugs able to overcome this escape route. The best known checkpoint pathways are the CTLA-4 and PD-1/PD-L1; they suppress T-cell activity in different ways: CTLA-4 regulates T-cell activity at an early stage whereas PD-1 regulates later effector T-cell activity within tissue and tumors. The best characterized checkpoint inhibitors in advanced NSCLC setting are ipilimumab and tremelimumab, (anti-CTLA-4 antibodies), nivolumab and pembrolizumab (anti-PD-1 antibodies), atezolizumab and durvalumab (anti-PD-L1 antibodies). Nivolumab and pembrolizumab have received the FDA and EMA approval for the treatment of NSCLC in second-line setting.

Expert commentary: The role played by tumor microenvironment may be the next area of research to overcome the resistance at the checkpoint inhibitors as well as the identification of biomarkers to better select patients. In addition checkpoint inhibitors are investigate in combination with other agent involved in immune control with promising results in solid tumors.     

进展期大肠癌免疫疗法的研究进展

目前,进展期大肠癌治疗缺乏有效手段,亟待研发新的治疗技术。近年来,免疫疗法已在血液系统肿瘤和黑素瘤的治疗中显示有显著疗效,且有多项免疫治疗技术试用于大肠癌治疗,包括肿瘤治疗性疫苗、免疫检查点抑制剂和过继细胞疗法等。其中,免疫检查点抑制剂抗程序性细胞死亡受体-1抗体已在DNA错配修复缺陷型大肠癌的治疗中显示有很好的疗效,但在血液系统肿瘤治疗中显示有显著疗效的嵌合抗原受体修饰的T细胞疗法却在大肠癌等实体瘤治疗中显示疗效欠佳,有一系列的问题需予解决。不过,免疫疗法已成为继手术、放疗和化疗后的第四大肿瘤疗法,将为进展期大肠癌治疗带来新的希望。     

Prospect of combination of anti-PD-1/PD-L1 therapy and other therapeutics for treatment of lung cancer

Lung cancer is the leading cause of cancer death worldwide, mainly because it has no obvious symptoms at the early stage and it is usually diagnosed at the advanced stage. Surgery and chemotherapy are the main common treatment options for lung cancer patients. During the past 25 years, great progress has been made in the treatment of lung cancer. Novel materials such as nanoparticles have shown therapeutic potential for lung cancer as they can selectively enter tumor cells due to their small size and surface modifiability. However,the prognosis of patients with lung cancer is still unsatisfactory. Targeted immunotherapy has shown potential for the treatment of lung cancer. The anti-tumor immunotherapy has been widely concerned as immune escape plays an important role in the occurrence and development of tumors. In particular, agents targeting PD-1/PD-L1 have been widely studied and some anti-PD-1/PD-L1 agents have been approved for the treatment of lung cancer by FDA since they have shown significant anti-tumor activity in lung cancer patients. Nevertheless, not all patients response to this therapy and the immune-related adverse events have emerged. The immune-related adverse events mainly involve the gut, skin, endocrine glands, liver,lung and other tissues. With the development of this field, combination therapy has been regarded as a promising strategy to improve the safety and efficacy of antiPD-1/PD-L1 therapy. Studies have shown that the radiotherapy, chemotherapy, oncolytic virus, antiangiogenic agents and indoleamine 2,3-dioxygenase(IDO) inhibitors may improve the efficacy and reduce the incidence of adverse events of anti-PD-1/PD-L1 therapy. Radiotherapy can not only kill tumor cells, but also stimulate the immune system by releasing tumor antigens. Chemotherapy may induce the tumor-specific adaptive immune response.Oncolytic virotherapy, which is a form of immunotherapy,can kill tumors directly and induce the host immune response to tumour cells. Angiogenic factors have immunosuppressive effect, thus the antiangiogenic drugs may improve anti-tumor activity of anti-PD-1/PD-L1 agents in the treatment of lung cancer. Researches on IDO inhibitors in combined with other therapies are active and this combination may have good safety. In this review, we summarized the mechanisms and advantages of the combination therapy based on anti-PD-1/PD-L1 therapy,providing basis for its further clinical application.     

Recent advances in the liposomal nanovesicles based immunotherapy in the treatment of cancer: A review

Immunotherapy, along with chemotherapy, targeted delivery, radiation and surgery has become one of the most common cancer treatments. The aim of cancer immunology is to use the bodys immune system to combat tumors and develop a robust antitumor immune response. In the last few years, immune checkpoint inhibitors and chimeric antigen receptor-modified T cells have made substantial advancements in cancer immunotherapy. By boosting cell type-specific delivery and immunological responses, nanocarriers like liposomes have the ability to enhance greater immune responses. The efficacy of anti-tumor therapeutics is being significantly improved as liposomes can assist in resolving a number of issues that can arise from a variety of cancer immunotherapies. Since, liposomes can be loaded with both hydrophilic and hydrophobic drugs and protect the immunotherapeutic agents loaded inside the core, they offer significant advantages over other nano delivery systems. The use of liposomes for accurate and timely delivery of immunotherapies to particular targeted neoplasms, with little or no injury to healthy cells, maximizes immunotherapy efficacy. Liposomes are also suitable vehicles for delivering medications simultaneously with other therapies such as chemotherapy, radiation, and phototherapy. Liposomal nanoparticles will be introduced and used as an objective immunotherapy delivery system for great precision, making them a viable cancer treatment approach.With an emphasis on dendritic cells, T cells, tumor and natural killer cells, and macrophages; outline of many forms of immune-therapies in oncology and cutting-edge advances in liposomal nanovesicles for cancer immunotherapy are covered in this review.     

Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona

There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8⁺ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).KEY WORDS: Tumor immune microenvironment, Tumor-associated macrophage, Epigenetic therapy, Immune checkpoint, Angiogenesis, Panobinostat, JQ1, Liposome     

Recent advances in,and challenges of,anti-angiogenesis agents for tumor chemotherapy based on vascular normalization

A major problem associated with cancer treatment is resistance-prone chemotherapeutic drugs. An increasing number of studies have documented that the occurrence of resistance tends to be associated with abnormal blood vessels. In 2001, Jain proposed the vascular normalization theory, which was recently applied to the drug-resistant treatment of tumors in the clinic. Through the intervention of angiogenesis inhibitors, remodeling the structure and function of abnormal vessels can maximize the efficacy of chemotherapeutic drugs. In this review, we systematically describe the occurrence and progress of tumor angiogenesis, as well as the pathological characteristics of tumor blood vessels. Moreover, druggable targets for vascular normalization and the development of related inhibitors are also outlined.     

免疫检查点阻断剂治疗膀胱癌的研究进展

膀胱癌是泌尿系最常见的恶性肿瘤,其特点是易复发,复发后恶性度增加.免疫检查点阻断剂通过调整机体的免疫系统功能,抑制肿瘤细胞免疫逃逸,使T细胞活化并清除肿瘤细胞.近年来,免疫检查点阻断剂已被用于治疗各种侵袭性肿瘤,这给膀胱癌的治疗提供了新思路.该文主要介绍免疫检查点阻断剂在膀胱癌治疗中的应用.