PD-L1和VEGF双靶点联合阻断治疗的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)通过阻断负调控免疫信号激活宿主抗肿瘤免疫反应。临床试验表明,ICIs的治疗能够明显引起部分晚期癌症患者的肿瘤消退。在临床实践中,ICIs治疗的一个主要问题是药物应答率低。尽管PD-L1表达、错配修复缺陷、肿瘤浸润性淋巴细胞状态等多种预测生物标志物已被用于筛选对治疗有应答的患者,但ICIs单药治疗的耐药性仍存在。近期研究表明,联合抗VEGF治疗可以减轻ICIs的耐药性。VEGF能抑制肿瘤生长和转移所必需的血管生成,同时能够对肿瘤免疫微环境进行重编程,减轻ICIs的耐药性。目前已针对此双靶点的联合治疗开展了很多临床试验,并获得了令人振奋的结果。对抗PD-L1联合抗VEGF治疗的作用机制以及PD-L1/VEGF联合阻断治疗的临床研究进行了综述汇总。     

基于细胞膜和细胞的仿生递药系统改善肿瘤免疫治疗效果

肿瘤免疫治疗已成为各种原发性和转移性癌症的有效治疗方式。纳米药物递送系统(nano drug delivery system, NDDS)具有生物利用度高、靶向性好的优点,在肿瘤靶向治疗和免疫治疗等方面受到广泛关注。然而,传统的NDDS在临床应用中存在易被免疫系统识别和清除、跨越生物屏障能力差等问题。仿生药物递送系统(biomimetic drug delivery system, BDDS)以其良好的生物相容性和较低的免疫原性成为新一代极具前景的治疗策略。哺乳动物的细胞(如红细胞、血小板、单核细胞、巨噬细胞、中性粒细胞和T淋巴细胞等)及其细胞膜源于母体生物系统,具有独特的生物学特征,成为研究的热点。该文综述了近年来基于细胞膜和细胞的BDDS在改善肿瘤免疫治疗中的最新进展,重点介绍了这些BDDS的构建方式、表征手段和应用研究,并对其在改善肿瘤免疫治疗效果领域面临的挑战及未来的发展进行了讨论。     

核酸适配体在肿瘤免疫治疗中的应用

核酸适配体是指通过指数富集的配体系统进化技术(systematic evolution of ligands by exponential enrichment, SELEX)技术得到的一种可以高特异性、高亲和性识别靶标物质的单链DNA或RNA,可以作为靶向性治疗的分子探针。指数富集的配体系统进化技术即SELEX技术是在体外合成一个随机序列的文库,通过4个步骤孵育、分离、回收、扩增即可获得相对应的核酸适配体。通过几十年的发展,如今SELEX技术已成为一种重要的研究手段。核酸适配体具有稳定性强、分子量小、易进行化学合成和修饰、能特异性结合包括从小分子到细胞等靶标,识别范围广等优点,被广泛应用在肿瘤领域。免疫治疗与传统的肿瘤治疗方式不同,它是增强机体自身免疫系统来达到清除体内肿瘤细胞的一种方式,已被临床证明是治疗多种癌症的有效方法,例如针对免疫检查点CTLA4和PD-L1/PD-1的抗体,临床试验取得了成功,这为肿瘤的治疗带来了新的思路方法。目前,相关的免疫治疗药物已经上市应用于临床治疗,但是通过免疫治疗获益的肿瘤患者相对较少且会产生严重的副作用。核酸适配体与免疫相结合,为肿瘤的治疗提供了一种新的研究思路。本文总结了近年来针对免疫系统筛选获得的核酸适配体及其在肿瘤免疫治疗中的应用。     

抗血管生成治疗联合免疫检查点抑制剂 在NSCLC中的研究进展

血管生成是非小细胞肺癌(NSCLC)生长、复发和转移的关键环节。抗血管生成治疗可以通过使肿瘤血管及微环境正常化,改善肿瘤血供和含氧量,增强放、化疗效果。也可以抑制肿瘤内毛细血管生长,使肿瘤细胞进入休眠状态,并诱导其凋亡。因此,靶向抗血管生成已成为NSCLC治疗研究的主要方向。贝伐珠单抗和雷莫芦单抗已被批准用于联合一线标准化疗治疗局部晚期或转移性NSCLC。然而,在这一治疗过程中,肿瘤会逐渐对抗血管生成药物产生耐药,这可能与肿瘤微环境(tumor microenvironment,TME)的改变有关。最近,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)已经取得了相当大的成功,但是反应率仍然被认为不是最佳的。因此,为了提高疗效,各种组合疗法正在测试中。临床前数据表明促血管生成因子具有免疫抑制作用,为ICI和抗血管生成药物联合使用提供了合理的解释。并且有研究认为,抗血管生成治疗与肿瘤免疫治疗相联合可能是一种相互增益的治疗策略。     

PD-L1降解途径与肿瘤免疫治疗

程序性死亡受体配体1 (programmed death ligand 1, PD-L1)是肿瘤免疫检查点阻断治疗中的重要靶点,其在多种细胞中均有表达。肿瘤细胞可通过高表达PD-L1来增强程序性死亡受体1 (programmed death 1, PD-1)抑制信号,从而促进肿瘤免疫逃逸。近年来,以抗PD-1/PD-L1抗体为代表的肿瘤免疫治疗给癌症治疗带来了革命性的变化。然而,肿瘤免疫治疗仅能对部分患者产生持久的疗效,多数患者对肿瘤免疫治疗的应答短暂或没有应答。研究发现, PD-L1的降解对肿瘤免疫治疗应答至关重要。本文综述了PD-L1的溶酶体降解途径、蛋白酶体降解途径及PD-L1降解与肿瘤免疫治疗的相互作用,旨在为进一步增强肿瘤免疫治疗的应答率和应答范围提供研究思路。     

全球肿瘤免疫治疗药物研发态势

正肿瘤免疫治疗被称为继手术、化疗、放疗后第4种疗法,其可激活特异性的免疫细胞,直接靶向性攻击癌症细胞,具有较高的疗效和安全性,是目前全球肿瘤治疗研究的热点。截至2016年4月15日,全球各医药企业和研究机构已针对CTLA-4、PD-1、PD-L1三个靶标进行了近115种肿瘤免疫治疗的生物技术药物的研发,文章就其中肿瘤免疫治疗药物的主要靶标、开发企业及市场前景等进行了分析。     

PD-1及其配体在非小细胞肺癌中的研究现状与展望

摘要：肺癌是全球最常见肿瘤之一,其中非小细胞肺癌（NSCLC）约占肺癌的85%。目前肺癌的治疗手段仍然有限,并且晚期肺癌的预后较差,严重影响患者的生命健康。程序性死亡受体1（PD-1）及其配体程序性死亡配体1（PD-L1）属于CD28/B7家族的共刺激分子,可负性调控T细胞免疫功能,使肿瘤细胞免于机体免疫系统的监视和清除。以PD-1/PD-L1单抗为代表的免疫治疗成为继手术治疗、化疗、放疗、分子靶向治疗之后的新焦点,针对PD-1/PD-L1通路的靶向治疗药物纳武单抗（Nivolumab）、派姆单抗（Pembrolizumab）已被食品药品管理局（FDA）批准投入临床使用,且已被国家综合癌症网络（NCCN）推荐为转移性肺癌的一线治疗药物。本文就PD-1/PD-L1的生物学结构及其在NSCLC中的作用机制、靶向药物、研究现状及展望展开综述。     

重组抗体工程及其在肿瘤靶向及癌症治疗中的应用

在过去的十几年中,重组抗体工程在基础研究、医学和药物生产上已经成为最有希望的领域之一。重组抗体及其片段在正在进行诊断和治疗的临床试验中占所有生物蛋白的30％以上。研究集中在抗体作为理想的癌症靶向试剂方面,最近由于FDA批准使用第一个工程化治疗抗体而使热度达到极点。过去的几年中,在设计、筛选及生产新型工程化抗体方面已经取得了重大进展。改革的筛选方法已经能够分离出高亲和力的癌－靶向及抗病毒的抗体,后能够抑制病毒用于基因治疗。癌症诊断和治疗的另一个策略是将重组抗体片段与放射性同位素、药物、毒素、酶以及生物传感器表面进行融合。双特异性抗体及相关融合蛋白也已经生产出来用于癌症的免疫治疗,在抗癌疫苗以及T细胞补充策略上有效地增强了人免疫应答。     

CIAPIN1基因与肿瘤

细胞因子诱导的凋亡抑制因子1(cytokine induced apoptosis inhibitor1,CIAPIN1)是最新发现的一个细胞因子依赖性抗凋亡分子,并已经被证实是独立于Bcl家族、胱天蛋白酶(caspase)家族等之外的Ras信号转导通路中的另一个调节分子。CIAPIN1广泛分布于胎儿和成人的正常组织中,特别在分化型组织和活性代谢组织中具有很高的表达水平,但是在某些癌症发生时表达受到抑制。通过基因转染、RNA干扰等技术手段研究CIAPIN1与肿瘤发生、发展的关联,揭示了CIAPIN1表达水平的改变与肿瘤进展具有相关性,CIAPIN1有望成为一个新的肿瘤治疗靶分子。     

基于铁死亡的抗结直肠癌药物的应用

结直肠癌（colorectal cancer，CRC）是癌症相关死亡的第二大主要原因，且患者趋于年轻化，化疗、免疫治疗及靶向治疗等药物治疗虽然取得进展，但因药物的毒性、耐药及价格昂贵严重影响CRC的综合治疗效果，因此寻求新的、更敏感有效的药物和药物靶点是目前研究的热点。铁死亡作为一种近期发现的细胞死亡调节方式，它与癌症药物耐药性、敏感性密切相关，激活铁死亡成为克服传统癌症治疗耐药机制的潜在策略，诱导铁死亡的药物研发应用有望成为治疗CRC的有效手段。本文综述在CRC中铁死亡相关代谢途径药物研究的最新进展，以便整体认识基于铁死亡的药物在CRC中作用的具体机制，充分发掘其治疗潜力，为CRC的诊疗和耐药性的解决提供新的思路。     

胶质瘤的免疫治疗策略及进展

胶质瘤是最常见的原发性颅内肿瘤之一,具有较高的发病率及死亡率。目前,传统的手术治疗辅助放化疗效果不佳。肿瘤的免疫治疗作为一种新兴的疗法在胶质瘤的治疗中已经取得了一定的疗效。本文将全面的总结归纳胶质瘤的三类免疫治疗方法:主动免疫疗法、被动免疫疗法和免疫调节疗法的内容以及现阶段的进展,并提出胶质瘤的免疫治疗潜在的问题:如接受免疫治疗的患者的免疫状态评估体系不健全、缺乏个性化治疗手段、经济效益以及伦理等问题。同时本文将提出免疫治疗在胶质瘤应用上的展望:1)采用手术治疗、放化疗与免疫治疗相结合的立体式鸡尾酒疗法,在增强各种治疗方法疗效的同时弥补传统治疗方法的不足;2)寻找合适的免疫治疗靶点;3)重点研究结合了过继性细胞免疫治疗与体液免疫治疗优势的治疗方法:嵌合抗原受体修饰的T细胞治疗胶质瘤。     

化疗相关性闭经的影响因素及临床利弊

针对恶性肿瘤的化学治疗源于上世纪40年代Philips与Gilman第一次使用氮芥治疗恶性肿瘤,发展至今化疗在恶性肿瘤的治疗过程中已经取得了非常大的进步,成为恶性肿瘤的主要治疗方法之一。随着新药的逐渐研发和使用,已经使多数恶性肿瘤患者得到生存期的延长甚至是治愈。然而化疗导致的多种不良反应却日益受到越来越多的关注,如严重的骨髓抑制、心脏功能及结构的损伤、恶心、呕吐、腹泻、掉发等。化疗药物对多种身体多种器官系统都存在伤害,这其中因化疗引起的卵巢功能损伤导致的闭经是女性患者中最常见的,并且与治疗有关的不良事件之一。因化疗所导致的卵巢功能损害不仅严重影响患者的生活质量,而且还可能导致某些严重的疾病。因此探讨其发生规律和防治方法有重要意义。     

用于肿瘤治疗的免疫检查点抑制剂相关预测生物标志物的研究进展

恶性肿瘤是严重威胁人类健康和社会发展的疾病。传统的肿瘤治疗方法如手术、放疗、化疗和靶向治疗等不能完全满足临床治疗的需求,新兴的免疫治疗成为了肿瘤治疗领域的研究热点。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一种肿瘤免疫治疗方法,已获批用于治疗多种肿瘤,如肺癌、肝癌、胃癌和结直肠癌等。然而,ICIs在临床使用过程中,只有少数患者会出现持久反应,一些患者还会出现耐药和不良反应。因此,预测生物标志物的鉴定和开发对提高ICIs的治疗效果至关重要。肿瘤ICIs预测生物标志物主要包括肿瘤生物标志物、肿瘤微环境生物标志物、循环相关生物标志物、宿主环境生物标志物以及组合生物标志物等,对患者筛查、个体化治疗和预后评估具有重要意义。本文就肿瘤ICIs治疗预测生物标志物的前沿进展作一综述。     

Proteomics and biomarkers in clinical trials for drug development

Proteomics allows characterization of protein structure and function, protein-protein interactions, and peptide modifications. It has given us insight into the perturbations of signaling pathways within tumor cells and has improved the discovery of new therapeutic targets and possible indicators of response to and duration of therapy. The discovery, verification, and validation of novel biomarkers are critical in streamlining clinical development of targeted compounds, and directing rational treatments for patients whose tumors are dependent upon select signaling pathways. Studies are now underway in many diseases to examine the immune or inflammatory proteome, vascular proteome, cancer or disease proteome, and other subsets of the specific pathology microenvironment. Successful assay verification and biological validation of such biomarkers will speed development of potential agents to targetable dominant pathways and lead to selection of individuals most likely to benefit. Reconsideration of analytical and clinical trials methods for acquisition, examination, and translation of proteomics data must occur before we march further into future of drug development.     

Need for aligning the definition and reporting of cytokine release syndrome (CRS) in immuno-oncology clinical trials

As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g., monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk–benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed.     

Biomarkers of clinical responsiveness in brain tumor patients : progress and potential

Gliomas are the most common primary brain tumors in adults. Anaplastic astrocytoma and glioblastoma multiforme represent malignant astrocytomas, which are the most common type of malignant gliomas. Despite research efforts in cancer therapy, the prognosis of patients with malignant gliomas remains poor. Research efforts in recent years have focused on investigating the cellular, molecular, and genetic pathways involved in the progression of malignant gliomas. As a result, biomarkers have emerged as diagnostic, predictive, and prognostic tools that have the potential to transform the field of brain tumor diagnostics. An increased understanding of the important molecular pathways that have been implicated in the progression of malignant gliomas has led to the identification of potential diagnostic, prognostic, and predictive biomarkers, some bearing clinical implications for targeted therapy. Some of the most promising biomarkers to date include loss of chromosomes 1p/19q in oligodendrogliomas and expression of O-6-methylguanine-DNA methyltransferase (MGMT) or epidermal growth factor receptor (EGFR) status in glioblastomas. Other promising biomarkers in glioma research include glial fibrillary acidic protein, galectins, Kir potassium channel proteins, angiogenesis, and apoptosis pathway markers. Research into the clinical relevance and applicability of such biomarkers has the potential to revolutionize our approach to the diagnosis and treatment of patients with malignant gliomas.     

Engineering T cells for immunotherapy of primary human hepatocellular carcinoma

Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4~(th) most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes(TCRTs) and the chimeric antigen receptor genes(CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.     

The Relationship of Immune Cell Signatures to Patient Survival Varies within and between Tumor Types

Enhancing pre-existing anti-tumor immunity leads to therapeutic benefit for some patients, but why some tumors are more immunogenic than others remains unresolved. We took a unique systems approach to relate patient survival to immune gene expression in >3,500 tumor RNAseq profiles from a dozen tumor types. We found significant links between immune gene expression and patient survival in 8/12 tumor types, with tumors partitioned by gene expression comprising distinct molecular subtypes. T/NK cell genes were most clearly survival-related for melanoma, head and neck, and bladder tumors, whereas myeloid cell genes were most clearly survival-related with kidney and breast tumors. T/NK or myeloid cell gene expression was linked to poor prognosis in bladder and kidney tumors, respectively, suggesting tumor-specific immunosuppressive checkpoints. Our results suggest new biomarkers for existing cancer immunotherapies and identify targets for new immunotherapies.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.