放疗与免疫治疗联合应用的相关机制及研究进展

放疗主要通过对放射野内肿瘤细胞的杀伤来提高肿瘤的局部控制、降低远处播散并能够激活机体抗肿瘤免疫应答,在免疫治疗的辅助下发挥全身抗肿瘤的作用。放疗联合免疫治疗作为一种新的治疗方式在部分转移性癌症患者中取得了显著疗效。在放射线杀伤局部肿瘤细胞的过程中,肿瘤相关抗原释放表达增加、肿瘤免疫抑制微环境得到改善、激活特异性T细胞免疫应答促使肿瘤细胞形成原位疫苗,合适的放疗剂量与分割模式在最佳时机联合相应的免疫治疗可杀伤放疗野外的远处转移病灶。本文对放疗促进抗肿瘤免疫反应的具体机制以及两者联合应用的广阔前景和面临的挑战进行综述。      

锌指蛋白调控肿瘤免疫原性的作用及其机制的研究进展

寻找对肿瘤免疫原性具有关键调控作用的生物治疗靶点是抑制肿瘤免疫逃逸、提高肿瘤免疫治疗效果的关键。锌指蛋白（ZFP）通过与DNA、RNA、蛋白质的相互作用,调控肿瘤抗原的形成、肿瘤表面MHC分子及其共刺激分子的表达、损伤相关分子模式的释放等,影响肿瘤细胞的免疫原性及肿瘤微环境（TME）中免疫细胞的分布和功能,进而在调节抗肿瘤免疫应答和肿瘤免疫逃逸中发挥重要作用。近年来,临床前及临床研究探索将ZFP 相关的生物治疗方法应用于肿瘤免疫治疗,主要聚焦在免疫检查点阻断治疗、免疫细胞治疗,以及免疫治疗联合治疗策略展现出了可喜的应用前景。     

肿瘤免疫治疗的研究进展和发展趋势

随着免疫学技术的进步,大量肿瘤抗原不断被发现。DC摄取肿瘤抗原诱导免疫激活还是抑制,取决于肿瘤细胞释放危险信号（GMCSF、单核趋化蛋白1、MCP1及热休克蛋白等）还是抑制性信号（TGFβ、IDO和iNOS等）。在危险信号的调节下,激活Th1细胞免疫应答清除肿瘤;而在抑制性信号的作用下,激活Th2应答,不能有效清除肿瘤。肿瘤免疫治疗方面的进展主要表现在抗体疗法、T细胞疗法及肿瘤疫苗。目前至少有7种抗体与化疗药物合用的临床效果已经被证实;尽管抗不同种癌症的抗体种类在逐渐增加,但还需进一步探讨用于抗体治疗的新靶点、开发新抗体及扩大抗体应用的抗肿瘤范围。而T细胞疗法治疗效果不十分理想。大多数肿瘤疫苗处于Ⅰ期和Ⅱ临床试验,但为数不多的Ⅲ期临床试验结果不理想,尚需进一步完善。抗体在免疫监视中的重要作用被逐渐认识,肿瘤免疫预防最终可能成为现实。     

免疫治疗联合化疗在胃癌治疗中的研究进展

[摘要] 胃癌患者具有相对较高的突变负荷、新抗原基数和肿瘤浸润淋巴细胞,表明其对免疫治疗可能具有潜在应答性,但多项研究显示,免疫检查点程序性死亡受体1（programmed death protein1, PD-1）抑制剂单药治疗应答率仅为10%~26%。近期,人们对化疗对机体免疫系统的影响进行了深入探究,证实化疗药物可通过不同免疫调节机制对肿瘤免疫应答产生影响。多项研究显示,免疫治疗联合化疗药物在提高患者客观缓解率（ORR）和延长生存期方面具有一定成效,联合方案逐渐成为目前晚期胃癌研究的热点。本文主要阐述化疗药物对肿瘤免疫应答的影响、免疫治疗联合化疗在晚期胃癌中的应用及预测疗效的生物标记物的进展,以期为胃癌的临床治疗提供参考。     

非小细胞肺癌的免疫治疗:改善患者预后的新方法

简介通常,非小细胞肺癌(non-small cell lung cancer,NSCLC)诊断已为晚期,且预后较差。目前的NSCLC标准治疗总体治愈率低,有必要开发新的治疗方法。我们在本综述中提供了最新的免疫治疗干预临床数据,该手段可能能够提高免疫系统对细胞的应答。方法我们针对临床应用免疫疗法治疗NSCLC,检索了PubMed上的文章以及最近肿瘤学术会议上的摘要。结果Ⅱ期临床研究结果表明,靶向肿瘤细胞本身或其异常表达的肿瘤标志物的疫苗治疗(mucin1,黑色素瘤相关抗原3,或表皮生长因子),有望作为NSCLC免疫疗法。非抗原免疫治疗,如抗细胞毒T淋巴细胞抗原4单克隆抗体、talactoferrin alfa和toll-样受体9拮抗剂,作用于激活的免疫系统,与肿瘤抗原无关,可用于晚期NSCLC的治疗。目前一些免疫治疗正在进行III期研究,以确定最佳治疗方案,并与NSCLC标准治疗对照,确定其临床疗效。结论越来越多的证据表明肺部肿瘤存在免疫应答。免疫治疗,包括疫苗治疗和非抗原免疫调节方法,可改善NSCLC的预后。而且,提高抗肿瘤免疫应答的治疗,与化疗有协同作用。生物标志物的明确以及免疫治疗作用机制的进一步阐明对于确定哪些患者更可能从免疫治疗中获益至关重要。     

针对MAGE-3抗原的DC肿瘤疫苗的研究进展

树突状细胞(dendritic cell,DC)作为体内功能最强的专职抗原提呈细胞,广泛分布于各种组织器官中,在激活肿瘤特异性免疫中发挥重要作用。黑素瘤相关抗原3(melanoma-associated antigen 3,MAGE-3)是一种肿瘤-睾丸抗原(cancer-testis antigen,CTA),属于黑素瘤相关抗原家族(melanoma-associated antigen family,MAGE family),在上皮细胞来源的多种肿瘤细胞表面都有不同程度的表达。MAGE家族类肿瘤表面标志物能被用于早期发现肿瘤细胞,并针对该类抗原进行特异性的免疫治疗,是肿瘤免疫治疗的理想靶抗原。由于DC能将肿瘤相关性抗原提呈给T淋巴细胞,产生抗原特异性免疫反应,因此DC肿瘤疫苗为肿瘤免疫治疗提供了一种有效手段。目前,针对MAGE-3抗原的DC肿瘤疫苗研究已经广泛开展,可以通过多种不同的方式将MAGE-3负载DC,并取得了一定的临床疗效,为DC肿瘤疫苗的临床应用带来了曙光。     

实体瘤免疫治疗的非常规反应及其疗效评价标准的研究进展

随着免疫学及分子生物学的发展,免疫治疗已成为抗肿瘤治疗的一种新模式。特别是免疫检查点抑制剂的临床应用日益广泛,并在多种实体瘤治疗中展现出优良前景,被视为最具有潜力抗肿瘤治疗方式之一。但越来越多的证据提示,免疫治疗产生了不同于传统应答模式的非常规免疫反应模式,包括假性进展、延迟反应等;同时研究证实,传统的实体瘤治疗疗效评价标准往往无法准确捕捉此类非常规反应,从而难以正确评估免疫治疗疗效,这为临床工作带来了极大困扰与挑战。因此,新的实体瘤免疫治疗疗效评价标准亟待建立与完善,导致一系列免疫相关疗效评价标准被陆续提出。本文就实体瘤免疫治疗,主要是检查点抑制剂治疗的非常规反应模式及相关疗效评价标准研究发展和应用作一综述。     

肿瘤微环境与免疫治疗耐药的关系及应对

免疫治疗的革命性进展开创了肿瘤精准化治疗的新时代,为肿瘤患者带来了长期生存获益。然而,在临床实践中仍存在免疫治疗耐药等诸多挑战。肿瘤微环境（tumor microenvironment,TME）的动态抑制性变化、异质性等特点在肿瘤发生发展、恶性进展、免疫逃逸和治疗耐药中发挥重要作用。因此,了解免疫治疗与TME之间的相互作用不仅对剖析其作用机制至关重要,而且有助于为提高免疫治疗疗效提供新的途径。本综述就TME的起源、动态抑制性变化、异质性特点进行总结,介绍关于TME如何影响免疫疗效的研究进展,以期通过靶向TME角度或联合治疗方式寻求优化免疫治疗疗效的应对策略。     

局部晚期宫颈癌放疗结合免疫治疗的相关研究进展

局部晚期宫颈癌患者标准治疗方案为同步放化疗,短期疗效较好,但远期预后较差,易局部复发和远处转移,严重影响患者的生活质量及总生存期.近年来,免疫治疗成为国内外学者研究的热点,其可以激活机体自身的免疫系统,通过增强体内免疫细胞的数量及功能,从而特异性、持续地识别并消灭肿瘤细胞.放疗主要是对照射野内的肿瘤组织采用高能射线的方式精确杀死局部肿瘤组织,死亡后的肿瘤组织最终作为一种新抗原激活体内的抗肿瘤免疫反应.基于局部放疗与免疫系统的内在协同作用使放疗结合免疫治疗成为可能.本文就国内外在局部晚期宫颈癌放疗结合免疫治疗的广阔前景及面临的相关挑战进行综述.     

基于新抗原免疫疗效预测研究进展

近年来,新抗原被认为是人体免疫系统识别和触发有效抗肿瘤免疫应答的关键分子,具有高度的免疫原性。研究显示免疫检查点抑制剂的疗效与新抗原的数量相关。因此,新抗原相关的生物标志物可能预测免疫治疗的疗效。全文主要讨论程序性死亡配体1、肿瘤突变负荷、肿瘤新抗原负荷、循环肿瘤DNA和微卫星不稳定性等对免疫治疗的预测价值,新抗原的鉴定方法,以及基于新抗原免疫疗法的应用成果。但实施检测和治疗的过程中也会遇到一些阻碍,例如：检测生物标志物过程繁琐,新抗原疫苗的制作费用高昂等。未来研究者们还需不断探索,找到更有效的生物标志物,使更多的患者从中受益,实现个体化的精准治疗。     

树突状细胞临床治疗实体瘤：峰回路转

肿瘤免疫细胞疗法展现了良好的临床抗肿瘤前景。树突状细胞（DC）识别肿瘤抗原作为机体免疫响应的关键起始步骤,捕获肿瘤抗原后分化成熟,在淋巴结将抗原信号提呈给CD4+ T细胞、CD8+ T细胞等免疫细胞,激发抗肿瘤效应,应用于肿瘤治疗,尤其是实体瘤,被寄予厚望。但由于实体瘤TME复杂的结构特点、DC和T/B 细胞免疫响应的机制不清晰等问题犹如崇山峻岭摆在眼前,故未能形成关键理论和技术突破。以CAR-T 细胞为代表的精准细胞免疫疗法已表现出优势,但仍面临抗原选择瓶颈。DC治疗性疫苗在临床试验中表现出良好的疗效和安全性,随着DC在TME中关键作用机制的进一步揭示,研究者的目光重新聚焦在DC抗肿瘤效应,推动着DC与其他手段的联合疗法、工程化DC疫苗等实体瘤治疗方案从基础向临床转化,目前正迈入DC临床治疗实体瘤的新阶段。本文系统地对DC治疗实体瘤的临床研究进展、实体瘤TME中DC的种类及其抗肿瘤机制、工程化DC疫苗,以及面临的挑战和应对策略等问题进行了评述。     

Heat-shock protein vaccines as active immunotherapy against human gliomas

Modern advances in cancer immunotherapy have led to the development of active immunotherapy that utilizes tumor-associated antigens to induce a specific immune response against the tumor. Current methods of immunotherapy implementation are based on the principle that tumor-associated antigens are capable of being processed by antigen-presenting cells and inducing an activated cytotoxic T-lymphocyte-specific immune response that targets the tumor cells. Antigen internalization and processing by antigen-presenting cells, such as dendritic cells, or macrophages results in their surface association with MHC class I molecules, which can be recognized by an antigen-specific cytotoxic T-lymphocyte adaptive immune response. With the aim of augmenting current immunotherapeutic modalities, much effort has been directed towards enhancing antigen-presenting cell activation and optimizing the processing of tumor-associated antigens and major histocompatibility molecules. The goal of these immunotherapy modifications is to ultimately improve the adaptive specific immune response in killing of tumor cells while sparing normal tissues. Immunotherapy has been actively studied and applied in glioblastomas. Preclinical animal models have shown the feasibility of an active immunotherapy approach through the utilization of tumor vaccines, and recently several clinical studies have also been initiated. Recently, endogenous heat-shock proteins have been implicated in the mediation of both the adaptive and innate immune responses. They are now being investigated as a potential modality and adjuvant to immunotherapy, and they represent a promising novel treatment for human glioblastomas.     

实体瘤免疫治疗疗效评价标准

免疫治疗已经成为实体瘤除手术、放疗、化疗、靶向治疗之外的重要治疗手段。然而免疫治疗的作用机制不同于既往的治疗手段,它是通过激活机体的免疫效应而杀伤肿瘤细胞,达到肿瘤负荷的下降及生存期延长的目的。所以传统的世界卫生组织（WHO）疗效评价标准和实体瘤疗效评价标准（RECIST）也就很难对肿瘤免疫治疗的临床疗效进行准确解读,新的免疫疗效评价标准则涵盖了免疫疗效的各种表现形式,正逐渐应用于临床。     

Perspectives of SEREX-defined antigens in diagnosis and immunotherapy for gastric cancer

Gastric cancer is the most common malignancy in the world. Often diagnosed at advanced and unresectable stage, there is no curative treatment available for gastric cancer. Immunotherapy might be a promising alternative option. The key challenge in gastric cancer diagnosis and immunotherapy is to find an efficient target that not only provide early indication of the disease but also can upregulate the anti-tumor immune response in the cancer patients. Tumor-associated antigens(TAAs) expressed in tumor cells can elicit the immune response in autologous host and are related to changes during the disease process may fulfill this demanding. Now, Thousands of antigens have been discovered by a powerful method called SEREX(serological analysis of tumor antigen by recombinant cDNA expression libraries) and some of SEREX-defined antigens have been evaluated in clinical trails as vaccines for cancer immunotherapy. This review will provide information on the application of SEREX method in gastric cancer research and knowledge learned from these studies to develop antigen-specific diagnosis and therapy for gastric cancer.     

Vaccine therapies for patients with glioblastoma

Glioblastoma (GBM) is a high-grade glial tumor with an extremely aggressive clinical course and a median overall survival of only 14.6 months following maximum surgical resection and adjuvant chemoradiotherapy. A central feature of this disease is local and systemic immunosuppression, and defects in patient immune systems are closely associated with tumor progression. Immunotherapy has emerged as an important adjuvant in the therapeutic armamentarium of clinicians caring for patients with GBM. The fundamental aim of immunotherapy is to augment the host antitumor immune response. Active immunotherapy utilizes vaccines to stimulate adaptive immunity against tumor-associated antigens. A vast array of vaccine strategies have advanced from preclinical study to active clinical trials in patients with recurrent or newly diagnosed GBM, including those that employ peptides, heat shock proteins, autologous tumor cells, and dendritic cells. In this review, the rationale for glioma immunotherapy is outlined, and the prevailing forms of vaccine therapy are described.     

非小细胞肺癌免疫治疗生物标志物研究进展

非小细胞肺癌约占所有肺癌类型的75%~80%,5年生存率仅为15%。近年来人们对肺癌精准治疗的认识明显提高,但非小细胞肺癌的治疗仍面临挑战,驱动基因阴性患者的治疗方式十分有限,晚期患者的预后仍较差。免疫治疗药物可以通过阻断免疫检查点使抗肿瘤T细胞免疫反应恢复或增强,或者T细胞受体转导的T细胞免疫疗法靶向大部分的肿瘤特异性抗原从而起到抗肿瘤作用。目前,仅免疫检查点治疗的临床试验表明,非小细胞肺癌中非选择性人群的客观缓解率为10%~20%,仍有大部分患者不能从免疫治疗中获益,故优势人群的筛选仍十分重要。PD-L1是目前最常用的免疫治疗的疗效预测标志物,但仍存在一定的局限性,不能作为常规标志物应用于临床。另有相关研究表明：肿瘤突变负荷、肿瘤浸润淋巴细胞、微卫星不稳定等都是预测免疫治疗疗效的重要生物标志物。本文将对目前临床研究中关于免疫治疗的相关生物标志物新进展作系统综述。     

胶质瘤免疫治疗新进展

肿瘤免疫治疗是应用免疫学原理和方法,激发和增强机体抗肿瘤免疫应答,并应用免疫细胞和效应分子输注宿主体内,协同机体免疫系统杀伤肿瘤、抑制肿瘤生长。尽管免疫治疗尤其是免疫检查点治疗在黑色素瘤、肾细胞癌、非小细胞肺癌（nonsmall cell lung cancer,NSCLC）和血液系统恶性肿瘤已显示出抗肿瘤效应,但在恶性胶质瘤中,免疫治疗尚处于研究初期阶段,大量临床试验证明免疫治疗在胶质瘤中是可行且安全的。本文对免疫检查点、过继免疫以及肿瘤疫苗等免疫治疗策略的最新进展做一综述。      

Immune approaches to the treatment of breast cancer,around the corner?

Immunotherapy for the treatment of breast cancer can be categorized as either (a) specific stimulation of the immune system by active immunization, with cancer vaccines, or (b) passive immunization, such as tumor-specific antibodies (including immune modulators) or adoptive cell therapy that inhibit the function of, or directly kill, tumor cells. We will present the current information and the future perspectives of immunotherapy in patients with breast cancer, including the prognostic role of tumor infiltrating lymphocytes, immune signatures, targeted therapies modulating the immune system, and tumor antigen cancer vaccines. Active immunotherapy in breast cancer and its implementation into clinical trials have been largely a frustrating experience in the last decades. The concept that the immune system regulates cancer development is experiencing a new era of interest. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. Also, the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Major topics in the field of immunology deserve a response: what do we know about tumor immunogenicity, and how might we therapeutically improve tumor immunogenicity? How can we modulate response of the immune system? Is there any gene signature predictive of response to immune modulators? The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signaling pathways that regulate immune responses in the tumor microenvironment.     

基于免疫检查点PD-1的肿瘤免疫耐药机制及耐药后再治疗的策略

免疫治疗被认为是继手术、放疗和化疗后的第四种肿瘤治疗方法。近年来随着对免疫治疗特别是免疫检查点抑制剂研究的深入,PD-1/PD-L1通路抑制剂被批准用于许多癌种的治疗,但由于肿瘤细胞通过多种耐药机制规避免疫应答,免疫检查点阻断存在整体应答率低、原发或继发性耐药等难题。本文阐述了肿瘤免疫耐药的机制,探讨了耐药后再治疗的策略,为提高免疫检查点抑制剂的应答率、降低免疫耐药发生的概率提供理论和临床依据。