胃恶性肿瘤靶向治疗与免疫检查点治疗的新进展

近年来,胃恶性肿瘤的靶向治疗与免疫检查点治疗取得积极进展。靶向治疗药物的研究及应用取得突破,向着精准化方向迈进;免疫检查点治疗在胃恶性肿瘤中也展现了巨大的潜力,已有多个免疫检查点抑制剂陆续获批上市,此外多项新药临床试验也正在进行中。将实验室研究成果尽快转化为临床试验研究仍是我们努力的方向。     

晚期胃癌免疫检查点抑制剂治疗的临床研究进展

[摘要] 晚期胃癌治疗方法有限,预后较差。2017 年,针对程序性死亡蛋白-1（programmed cell death protein-1, PD-1）和程序性死亡配体-1（programmed death ligand-1, PD-L1）的免疫检查点抑制剂获批用于晚期胃癌治疗,提示胃癌免疫治疗时代已经到来。然而,相对于肺癌,免疫检查点抑制剂尚未获批用于胃癌一、二线治疗。目前,大量胃癌免疫治疗临床试验正在进行中,其模式还在进一步优化,包括免疫联合化疗、免疫检查点抑制剂联合其他免疫治疗及新型免疫检查点抑制剂的应用等,同时寻找合适的肿瘤标志物,筛选优势人群用于胃癌精准免疫治疗。本文着重讨论晚期胃癌免疫检查点抑制剂治疗的临床研究最新进展。     

热疗联合免疫检查点抑制剂的基础研究和临床应用进展北大核心CSCD

恶性肿瘤传统治疗方法对晚期转移患者疗效欠佳。近年来免疫检查点抑制剂治疗发展迅速,极具潜力,但整体临床有效率不高。肿瘤通过多种机制改变肿瘤微环境,产生免疫耐药,从而大大降低了免疫检查点抑制剂的疗效。热疗不仅可发挥热效应的抗肿瘤优势,还可通过多种途径起到直接和间接免疫增敏作用,将"冷肿瘤"转变为"热肿瘤",从而多方面起到增强免疫检查点抑制剂疗效的作用。大量基础实验证明,在小鼠体内进行热疗联合免疫检查点抑制剂已取得较好效果。目前,部分正在开展的热疗联合免疫检查点抑制剂临床试验也已取得较好进展。本文从免疫检查点抑制剂、热疗、热疗联合免疫检查点抑制剂3个层面分析了联用优势,并展望了未来热疗联合免疫检查点抑制剂治疗的重点研究方向。     

局部进展期结直肠癌新辅助免疫治疗临床研究及应用进展

局部进展期结直肠癌术后高复发风险使得患者长期生存面临挑战。免疫检查点抑制剂的出现使得许多恶性肿瘤的治疗发生了革命性的转变。目前,免疫检查点抑制剂已被批准用于不可切除的结直肠癌晚期的一线治疗,但其在新辅助治疗中的疗效和安全性的描述尚不多见。早期的临床试验已经初步证实了新辅助免疫治疗在局部进展期结直肠癌患者中的临床益处,进一步高质量的临床试验正在开展。本文就免疫检查点抑制剂在局部进展期结直肠癌新辅助治疗中的相关临床研究和应用进展进行梳理和总结,以期为结直肠癌新辅助免疫治疗的发展提供一定的参考。     

非小细胞肺癌免疫检查点阻断剂治疗进展*

目前大部分肺癌患者就诊时已是晚期,不宜手术切除,主要采用放疗、化疗和靶向治疗等综合治疗,5 年生存率较低。免疫检查点阻断剂通过调整机体的免疫系统功能,打破肿瘤细胞免疫逃逸机制,使T 细胞活化并清除肿瘤细胞,成为一种有效的肿瘤治疗方式。目前免疫检查点阻断剂在非小细胞肺癌（non-small celll ung cancer ,NSCLC ）临床试验中取得一定疗效,很多研究正在开展,这有可能改变NSCLC 的治疗模式。本文将阐述免疫检查点阻断剂在NSCLC 中的治疗作用及联合其他治疗的应用前景。     

食管癌的免疫治疗

肿瘤进展通常与免疫抑制或癌细胞逃避免疫监视相关.免疫治疗可提高免疫系统识别和清除肿瘤细胞的能力,且对正常组织影响轻微,是目前晚期食管癌研究的热点.食管癌的免疫治疗方法主要包括免疫检查点抑制剂、过继细胞免疫治疗、肿瘤疫苗和抗体治疗.目前大量临床试验正在进行中,以评价免疫治疗在食管癌中的作用.以Pembrolizumab和Nivolumab为代表的免疫检查点抑制剂在晚期食管癌治疗中已取得初步成功,为食管癌患者改善预后和生命质量带来希望.未来还需要对肿瘤异质性、疗效预测靶点、免疫治疗耐受等影响免疫治疗疗效的问题展开进一步的研究.     

化疗药物的免疫调节作用研究进展

化疗药物是治疗中晚期肿瘤的有效方法.近年的研究表明,化疗药物还具有免疫调节作用.部分化疗药物可以通过诱导肿瘤细胞免疫原性细胞死亡或者进行"免疫原性调节"增强抗肿瘤免疫.化疗药物还可以影响免疫细胞和肠道菌群.同时,多项化疗联合免疫检查点抑制剂(ICIs)的临床试验正在开展.本文深入探讨化疗药物的免疫调节作用以及化疗与IC...     

消化系统肿瘤“免疫治疗前移”的探索

免疫检查点抑制剂的出现为肿瘤治疗带来了新的曙光。免疫检查点抑制剂需要激活自身免疫对抗肿瘤细胞,因此,在患者免疫状态更好时使用免疫治疗可能会为患者带来更多获益。目前免疫治疗多用于肿瘤的后线治疗,但经过多线治疗的患者一般状态较差,免疫治疗的效果可能降低。“免疫治疗前移”指在肿瘤治疗的过程中前线应用免疫治疗,以期达到更好的治疗效果。本文就消化系统肿瘤中“免疫治疗前移”的背景、临床试验及待解决问题进行综述。     

新的免疫检查点分子在肿瘤中的研究进展

免疫检查点是调节T细胞免疫反应的免疫分子,主要分布在抗原呈递细胞、T细胞和肿瘤细胞表面.新的免疫检查点如B7-CD28、TIM-3、LAG-3、VISTA和CD40抑制剂正在研究.寻找新的免疫检查点抑制剂及其预测因子是未来肿瘤免疫治疗的方向.     

肿瘤微环境内代谢变化与肿瘤免疫治疗研究

肿瘤免疫疗法在肿瘤治疗领域取得重大进展.许多临床试验已经揭示了基于激活肿瘤特异性T细胞的免疫检查点抑制剂在肿瘤治疗方面的显著疗效.然而,只有部分癌症患者可以从免疫疗法中受益,越来越多的证据表明,可能是由于免疫抑制性肿瘤微环境(tumor mi-croenvironment,TME)的代谢重编程不足,使得抗肿瘤免疫力的恢...     

Immunotherapy: A New (and Old) Approach to Treatment of Soft Tissue and Bone Sarcomas

Soft tissue and bone sarcomas are a rare and heterogeneous form of cancer. With standard of care treatment options including surgery, radiation, and chemotherapy, the long‐term survival is still low for high‐risk soft tissue sarcoma patients. New treatment strategies are needed. Immunotherapy offers a new potential treatment paradigm with great promise. Immunotherapy of soft tissue sarcomas dates back to Dr. Coley's first use of toxins in the late 1800s. A variety of strategies of immunotherapy have been tried in soft tissue and bone sarcomas, including various vaccines and cytokines, with limited success. Results of these early clinical trials with vaccines and cytokines were disappointing, but there are reasons to be optimistic. Recent advances, particularly with the use of adoptive T‐cell therapy and immune checkpoint inhibitors, have led to a resurgence of this field for all cancer patients. Clinical trials utilizing adoptive T‐cell therapy and immune checkpoint inhibitors in soft tissue and bone sarcomas are under way. This paper reviews the current state of evidence for the use of immunotherapy, as well as current immunotherapy strategies (vaccines, adopative T‐cell therapy, and immune checkpoint blockade), in soft tissue and bone sarcomas. By understanding the tumor microenviroment of sarcomas and how it relates to their immunoresponsiveness, better immunotherapy clinical trials can be designed, hopefully with improved outcomes for soft tissue and bone sarcoma patients.

Implications for Practice

Immunotherapy is a promising treatment paradigm that is gaining acceptance for the management of several cancers, including melanoma, renal cell carcinoma, prostate cancer, and lung cancer. There is a long history of immunotherapy in the treatment of soft tissue and bone sarcomas, although with little success. It is important to understand past failures to develop future immunotherapy treatment strategies with an improved possibility of success. This article reviews the history of and current state of immunotherapy research in the treatment of soft tissue and bone sarcomas, with particular regard to vaccine trials, adoptive T‐cell therapy, and immune checkpoint blockade.     

免疫检查点抑制剂在软组织肉瘤治疗中的研究进展

软组织肉瘤(soft tissue sarcomas,STS)是一种具有多样生物学行为,来源于间质细胞的恶性肿瘤.STS的主要治疗手段为外科切除、联合新辅助或辅助放化疗.免疫检查点存在于免疫系统中的抑制性信号通路,是肿瘤实现免疫逃离的主要途径,目前已有多项利用免疫检查点抑制剂治疗恶性肿瘤的临床研究,并已取得了良好的效果...     

Pitfalls or promise in prostate cancer immunotherapy-which is winning?

PURPOSE: Immunotherapy with vaccines, cytokines, and monoclonal antibodies against checkpoint molecules has been introduced into the clinical arena. Although all have demonstrated safety in clinical trials in patients with castrate metastatic prostate cancer, no one approach has been able to provide improved overall survival. This article is a review of the current issues and potential resolutions as to how we might go forward in developing and interpreting immunologic trials. DESIGN: Phase I, II, and III trials showed that immunologic tolerance can be abrogated against specific tumor-associated antigens, but the immunologic readouts are suboptimal in determining whether a trial can go forward in its development. RESULTS: Combinatorial approaches appear to be necessary for inducing immunogenicity and antitumor effects. Strategies include irradiated tumor cells lines, costimulatory molecules, or immune checkpoint inhibitors, which are in trials and are under intense scrutiny as to their impact on clinical end points such as time to disease progression and survival. DISCUSSION: Strategies to enhance immunogenicity of vaccines and reassess how to effectively establish interpretable immunologic end points are under development and appear to be successful in affecting how these trials go forward.     

The treatment of resectable gastric cancer: a literature review of an evolving landscape

Background and ObjectiveGastric cancer carries a poor prognosis despite advances in treatment. Despite curative-intent surgery, the risk of recurrence is high. Perioperative treatment may improve rates of complete surgical resection and reduce the rate of recurrence. Treatment practices vary worldwide, while perioperative treatment is considered standard-of-care practice in Western countries, upfront surgery followed by adjuvant therapy is preferred in Asian countries. The current literature is complex to navigate with a plethora of studies available for review. The aim of this review is to summarise current evidence regarding the role of perioperative treatment in resectable gastric cancer and to explore future directions in research.MethodsWe searched the PubMed database for peer-reviewed original articles from phase III trials, published between 2002 to 2021 with regard to the treatment of resectable gastric cancer. Current active clinical trials regarding the use of targeted therapy and immune checkpoint inhibitors in perioperative and adjuvant therapy were identified using the ClinicalTrials.gov database from the US National Library of Medicine.Key Content and FindingsCompared to surgery alone, the use of perioperative chemotherapy prior to resection of gastric cancer and the use of adjuvant chemotherapy after upfront surgery both improve survival in those with resectable gastric cancer. However, treatment practices vary worldwide. In clinical practice, patient factors such as functional status should be considered when considering treatment approach. Many current clinical trials explore the role of targeted therapy and immune checkpoint inhibitors in the perioperative setting, which appear to be promising.ConclusionsGastric cancer continues to carry a poor prognosis. The addition of targeted agents and immune checkpoint inhibitors in the perioperative setting appear to be promising although further research is required in this area to assess efficacy. Further clinical research is required to identify new agents and approaches to treatment to improve the survival of these patients.     

复发转移性头颈鳞状细胞癌免疫治疗现状和探索

目的 世界范围内,头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)发病率在恶性肿瘤中居第7位,复发转移性(recurrent or metastatic,R/M) HNSCC生活质量下降,治疗方法少,预后差.近年来,以免疫检查点抑制剂为代表的免疫治疗取得突破性进展,成为黑色素瘤、肺癌等多种肿瘤有效的治疗选择.本研究对R/M HNSCC免疫治疗的现状和进展作一综述.方法 以“头颈鳞癌,免疫治疗,免疫检查点抑制剂,过继T细胞治疗,肿瘤疫苗”等为关键词,应用PubMed和CNKI期刊全文数据库检索系统以及ClinicalTrials.gov网站,检索2001-01-2017-01的相关文献及注册临床研究,共检索到英文文献138篇,中文文献84篇.纳入标准:(1)R/M HNSCC;(2)免疫治疗现状及进展;(3)免疫治疗相关临床研究.共纳入38篇文献进行分析.结果 R/M HNSCC中免疫治疗研究广泛开展并逐渐深入,尤其是免疫检查点抑制剂.程序性细胞死亡1(programmed cell death-1,PDq)抑制剂(Pembrolizumab和Nivolumab)显示出明显疗效,因此被食品药品管理局(food and drug administration,FDA)批准用于R/M HNSCC的治疗.尽管其他免疫检查点抑制剂如程序性死亡配体1(programmed death ligand-1,PD-L1)抑制剂(Durvalumab和Avelumab)和细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂(Ipilimumab和Tremelimumab)尚无Ⅲ期临床研究结果发表来证明其确切疗效,但有一系列临床研究正在进行中.过继T细胞治疗和肿瘤疫苗的免疫治疗模式也在探索中.此外,在R/M HNSCC免疫治疗中根据生物标志物筛选有效患者,联合治疗提高疗效以及不良反应的监测及治疗等方面也被关注.结论 R/M HNSCC中免疫治疗有良好前景,但也存在许多挑战,如何筛选免疫治疗最有效的人群、探索免疫治疗模式及提高疗效仍是未来研究重点.     

以NKG2A 为靶点的肿瘤免疫治疗：现状、问题与对策

自然杀伤细胞2 族成员A（NKG2A）为免疫细胞表面重要的免疫检查点,NKG2A 与其配体HLA-E 的结合会抑制NK 细胞和T 细胞的免疫效应功能,甚至使之发生功能耗竭,导致肿瘤细胞免疫逃逸。抗NKG2A 抗体可以通过阻断NKG2A 与其配 体的结合而恢复NK 细胞和T 细胞的功能,从而唤醒强大的抗肿瘤免疫。与其他免疫检查点（如PD-1、CTLA-4 等）相比,NKG2A 阻断性抗体在临床肿瘤治疗中具有其独特的优势,其阻断NKG2A 的识别及其信号通路,能够同时逆转T 细胞和NK 细胞的功能 耗竭,全面唤醒机体的抗肿瘤效应。基于NKG2A 的抗肿瘤免疫疗法正在开展多项临床试验,显示出良好的安全性和有效性。本 文就NKG2A 及其配体的表达与信号转导、NKG2A 介导免疫细胞的功能耗竭,以及目前以NKG2A 为靶点的肿瘤免疫治疗策略和 临床研究进展现状、存在问题和对策进行阐述,为以NKG2A 为靶点的肿瘤免疫治疗策略的开发和临床应用提供参考。     

Immune Checkpoint Blockade and Hematopoietic Stem Cell Transplant

Allogeneic hematopoietic stem cell transplant (HSCT) relies primarily upon graft-versus-tumor activity for cancer eradication. Relapse remains the principal cause of treatment failure after HSCT, implying frequent immune escape, which in at least some cases, appears to be mediated by increased expression of inhibitory immune checkpoints. In an attempt to restore anti-tumor immunity, checkpoint blockade therapy (CBT) targeting PD-1 and CLTA-4 has been used in conjunction with both allogeneic and autologous HSCT. Clinical experience in this setting is limited to several small clinical trials and case series, but together they suggest that treatment with CBT can effectively amplify anti-tumor immune responses. However, intrinsic to its mechanism is also the risk that CBT in the HSCT setting may also cause significant immune toxicity. Fatal immune-related adverse events and graft-versus-host disease have been observed, but in most cases, immune side effects appear to be reversible with steroids and CBT discontinuation. As clinical investigation continues, improved understanding of immune checkpoint biology will be critical to optimize safe and efficacious treatment strategies.     

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.     

免疫治疗联合放化疗治疗胶质母细胞瘤的研究进展

目前胶质母细胞瘤（glioblastoma,GBM）的标准治疗方法仍然是在最大安全程度的手术切除基础上辅以放化疗,但其5年生存率仍＜10%。免疫治疗如树突状细胞(dendritic cell,DC)疫苗、表皮生长因子受体突变体(EGFRvIII)疫苗、热休克蛋白（heat shock proteins,HSPs）疫苗等在临床试验中已经取得了巨大成就,临床III期试验也证明了免疫治疗与放化疗有协同作用。细胞毒性电离辐射是一种引起促炎信号级联免疫活化辅助细胞死亡的治疗方法,借此可以利用免疫治疗抗肿瘤。肿瘤免疫治疗的发展,使得免疫治疗可能成为继手术、放化疗后GBM治疗的另一个有效方法。寻找新的免疫治疗方法是未来GBM治疗的主要研究方向。本文就目前GBM的治疗策略及困境和放化疗联合免疫检查点抑制剂、DC疫苗以及EGFRvIII疫苗等免疫治疗研究进展作一综述。     

Current Status of Clinical Trials for Cervical and Uterine Cancer Using Immunotherapy Combined With Radiation

Novel therapies combined with radiation continue to be of significant interest in the developmental treatment paradigm of gynecologic cancers. Clinical implementation of immunotherapy in oncology has rapidly changed the treatment landscape, options, paradigm, and outcomes through clinical trials. Immunotherapy has emerged as a therapeutic pillar in the treatment of solid tumors with demonstrable synergistic activity when combined with radiation therapy and chemoradiotherapy by an alteration or enhancement of the immune system. In solid tumors, radiation therapy induces migration of dendritic cells, T cell activation, and proliferation, and increases in tumor-infiltrating lymphocytes. These immunomodulatory effects in conjunction with immune checkpoint blockade are currently under active investigation in the adjuvant, definitive, and metastatic settings. Results from early phase trials demonstrate promising efficacy and overall tolerable toxicity profiles of combined modality treatment. There is significant interest in optimizing the treatment for patients with locally advanced cervical cancer beyond the standard of care—chemoradiation—which has been in place for the last 30 years. The majority of cervical cancer emerges after persistent infection with a high-risk subtype of the human papillomavirus, where viral oncoproteins lead to cellular changes and immortalization. As a result, immune tolerance can develop, resulting in cancer. Knowledge of the mechanism of human papillomavirus–related oncogenesis suggests that immune therapy or checkpoint blockade can reinvigorate an antitumor immune response. Current clinical trials are exploring the therapeutic potential of these approaches. Uterine cancers have been grouped into 4 molecular subclasses by their driver mutations, mutational burden, and copy-number alterations. Of these subgroups, the polymerase epsilon–mutated and microsatellite-unstable may represent up to 40% of endometrial cancers, and they have been shown to be immunogenic. Because of the inherent immunogenicity of these MSI-high tumors, combined immune modulation strategies, including chemotherapy, radiation, and immunotherapy and immune checkpoint inhibitor therapy, are being explored to improve treatment outcomes. In this review, we explore current immunomodulatory and multimodality therapeutic approaches in the treatment of cervical and uterine cancer through ongoing clinical trials investigating the combination of immunotherapy and radiation therapy.