TIGIT和PD-1/PD-L1双重阻断途径在肿瘤免疫治疗中的研究进展

程序性死亡蛋白-1和程序性死亡蛋白配体-1(programmed death-1/programmed death-ligand 1,PD-1/PD-L1)作为一种抑制T细胞活化的调节性免疫检查点分子,在肿瘤的免疫治疗发挥着重要的作用。近年来,越来越多的靶向治疗药物得到研发,但是单一免疫检查点阻断剂并不能很好的抑制肿瘤的发生,肿瘤逃逸现象时有发生,而靶向药物的联合治疗可作为抑制肿瘤发生发展的重要手段之一。属于1型脊髓灰质炎病毒受体的抑制性受体T细胞免疫球蛋白和免疫受体酪氨酸抑制基序（immunoreceptor tyrosine-based inhibition motif,ITIM）结构域（T cell immunoglobulin and ITIM domain,TIGIT）是近年靶向药物治疗研究的热点,其与PD-1/PD-L1的联合治疗可减少肿瘤逃逸,更有效地抑制肿瘤的发生。因此,本文就TIGIT和PD-1/PD-L1双重阻断途径在肿瘤免疫治疗中的研究进展进行归纳总结,旨在肿瘤免疫治疗提供一定的理论依据。     

晚期NSCLC EGFR-TKIs治疗失败应用PD-1/PD-L1抑制剂进展

目的 探讨程序性死亡受体-1/程序性死亡受体配体-1(PD-1/PD-L1)抑制剂在表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)治疗失败的非小细胞肺癌(NSCLC)患者中的最佳治疗方案,为临床治疗提供参考。方法 使用PubMed及中国知网数据库检索系统,以“非小细胞肺癌、EGFR-TKIs耐药、PD-1/PD-L1抑制剂”为中文关键词,“non-small cell lung cancer、EGFR-TKIs resistance、PD-1/PD-L1 inhibitors”为英文关键词,检索2009-09-03-2022-06-02相关文献。纳入标准：PD-1/PD-L1抑制剂用于EGFR-TKIs治疗失败的晚期NSCLC患者的相关研究。排除标准：数据陈旧的相关研究。共纳入文献56篇。结果 PD-1/PD-L1抑制剂单药效果有限,联合EGFR-TKIs由于毒副作用大多停止用药,联合TGF-β及CTLA-4抑制剂或抗血管生成药物研究样本量有限,联合化疗或联合化疗及抗血管生成初见疗效,但联合方案的最优选择仍然存在争议。结论 PD-1/PD-L1抑制剂在EGFR-TKIs治疗失败...     

基于PD-1/PD-L1靶点的肿瘤免疫治疗研究进展

近年来的研究显示,肿瘤免疫治疗在恶性肿瘤的治疗上成效显著,疗效优于传统的化疗和放疗.程序性死亡受体-1(programmed death 1,PD-1)和程序性死亡受体配体-1(programmed death-ligand 1,PD-L1)这对免疫共抑制分子作为肿瘤免疫治疗的靶点备受关注,PD-L1在一些肿瘤细胞中的...     

PD-1/PD-L1抑制剂在前列腺癌免疫治疗中的研究进展

前列腺癌（prostate cancer,PCa）发病率呈逐年上升趋势,前列腺癌免疫治疗已成为继外科、放疗、化疗之后的第四种治疗方法。作为当今肿瘤免疫治疗领域最具有研究前景的免疫检查点抑制剂中的程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand1,PD-L1）抑制剂,通过阻断PD-1与其配体PD-L1结合,从而终止T细胞的负性调控信号,使T细胞的活性恢复,进而逆转肿瘤免疫逃逸机制,恢复自身免疫应答,最后起到抑制和杀伤肿瘤的作用。本文就目前应用于前列腺癌临床试验的PD-1/PD-L1抑制剂的现况和临床疗效研究进展进行综述。      

以PD-1和PD-L1为靶点的肿瘤免疫治疗研究进展

近年来,肿瘤免疫治疗取得了显著的进展,对肿瘤患者有良好的疗效,成为继手术、放疗和化疗后治疗恶性肿瘤的新模式。目前,程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)为靶点的免疫治疗是当前肿瘤免疫治疗的研究热点。PD-1是一种抑制T细胞炎性活动的细胞表面受体,属于B7-CD28受体家族成员,常在患者的T细胞中表达;PD-L1是B7家族中的共刺激信号分子,在多种肿瘤细胞和肿瘤组织中均有表达,PD-1/PD-L1通路在诱导效应T细胞凋亡、抑制T细胞活化、抑制机体抗肿瘤免疫反应和肿瘤免疫逃逸过程中发挥重要作用。目前以PD-1和PD-L1为靶点的肿瘤免疫治疗主要分为如下五类:小分子抑制剂、单克隆抗体、双特异性抗体、抗体药物偶联物以及细胞免疫治疗。本研究针对这五类治疗的最新进展进行综述。     

PD-1/PD-L1抑制剂及其疗效预测标志物在非小细胞肺癌中的研究进展更新

程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)免疫检查点抑制剂的发展为非小细胞肺癌(NSCLC)的治疗提供了新的方向.然而,疗效预测标志物的尚未确定在很大程度上限制了其有效应用.本文对美国食品药品监督管理局(FDA)批准、尚处于试验阶段的PD-1/PD-L1抑制剂的相关临床试验进行了综述.事实上,目前仅有约20％的晚期NSCLC患者可以从PD-1/PD-L1抑制剂中获益.多数临床试验将患者的PD-L1表达水平作为疗效预测标志物,但其预测价值不尽相同,本文亦对其临床应用局限性的原因进行了讨论.随着肿瘤突变负荷、肿瘤免疫微环境等新兴标志物的出现,将其与PD-L1表达相结合,指导PD-1/PD-L1抑制剂有效的个体化应用正逐渐成为新的研究方向.     

PD-1/PD-L1在肿瘤中的机制研究及其在甲状腺癌中的诊治价值

程序性死亡受体1(PD-1)和程序性死亡受体配体1(PD-L1)参与免疫检查点调节,与肿瘤的发生和发展密切相关。在甲状腺癌中,PD-L1的表达及PD-1阳性T细胞的增多可能预示着更高的侵袭性与更大的复发风险。抗PD-1/PD-L1治疗在许多肿瘤中已有显著疗效,但在甲状腺癌方面的疗效还比较局限,需要寻找能够更好预测疗效的生物标志物。进一步了解PD-1/PD-L1的作用机制及其在甲状腺癌中的诊治价值以及与其疗效相关的生物标志物,可为甲状腺癌患者提供新的治疗方法与思路。     

循环外泌体PD-L1表达水平与PD-1/PD-L1抑制剂治疗恶性肿瘤疗效的相关性研究现状

外泌体作为具有生物学功能的小囊泡,是近年肿瘤研究领域关注的热点。研究发现,肿瘤细胞分泌的外泌体表达的程序性死亡受体配体1(programmed death ligand 1,PD-L1),可在肿瘤患者外周血液中检测到,可能参与并抑制机体免疫反应。近年来,一些研究发现,外泌体PD-L1可能影响程序性死亡受体1（programmed death 1,PD-1）/PD-L1抑制剂的抑制效应。反之,亦然。应用PD-1/PD-L1抑制剂治疗,可影响外泌体PD-L1的表达水平。二者有怎样的联系和相关性？本文就循环外泌体PD-L1在不同肿瘤免疫反应及抗PD-1/PD-L1免疫治疗中的研究进展作一综述。     

PD-1/PD-L1抑制剂的剂量选择与优化

摘 要：肿瘤免疫治疗中，以程序性死亡受体1（programmed cell death protein 1，PD-1）/程序性死亡受体—配体1（programmed cell death-ligand 1，PD-L1）抑制剂为代表的免疫检查点单抗阻断治疗已逐渐成为肿瘤治疗领域的焦点。合理用药是使患者达到有效临床获益的重要环节，其中用药剂量准确是合理用药的关键。因此，充分了解PD-1/PD-L1抑制剂的药代动力学、药效学特点以及由此衍生的剂量选择和剂量优化方案对消除用药疑虑、增强用药依从性，从而实现规范化用药具有重要的临床意义。全文就PD-1/PD-L1抑制剂的剂量优化历程和临床应用进行综述，以期为PD-1/PD-L1抑制剂的临床规范使用提供参考。     

免疫检查点PD-1/PD-L1阻断剂耐药机制的研究进展

免疫检查点蛋白通过复杂机制抑制抗肿瘤免疫,进而介导恶性肿瘤的“免疫逃逸”。2018年诺贝尔生理学或医学奖的两位得主发现了抑制上述机制的癌症疗法,为人类抗肿瘤治疗带来曙光。近年来,针对程序性死亡受体-1（PD-1）/程序性死亡受体配体-1（PD-L1）的免疫检查点阻断治疗在多种恶性肿瘤中取得较好疗效,将肿瘤免疫治疗推向新的里程碑。然而继之出现的耐药问题,限制了其临床应用,成为这一领域新的难题。本文就PD-1/PD-L1阻断剂耐药现象及相关机制作一综述。     

Tumor regression after combination of radiation and PD-1 antibody nivolumab treatment in a patient with metastatic mediastinal leiomyosarcoma: a case report

The PD-1/PD-L1 axis is characterized as an important checkpoint of immune activation, particularly through negatively regulating T cell function. Although accumulated evidence has demonstrated the patients with some types of tumor benefit from blockade of PD-1/PD-L1 signaling pathway, the possible synergistic effect of combination of radiotherapy and anti-PD-1/PD-L1 antibody still need to be explored. Here, we report a case of patient who was diagnosed with metastatic mediastinal leiomyosarcoma and treated by combination of local radiotherapy and anti-PD-1 antibody nivolumab. Remarkable tumor regression was observed at both the irradiated focus and distant metastatic sites 2 months later after combined treatment. The patient has tumor mutational burden (8.7 somatic mutations/Mb) and positive PD-L1 expression. The increased circulating lymphocytes suggest induced activation of immune response after combination treatment. Free disease progression has reached one and a half years as far.     

Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non–Small-cell Lung Cancer: A Mini-review

Immune checkpoint inhibitors against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) are a standard pharmacologic therapy for patients with non–small-cell lung cancer (NSCLC). Substantial data have accumulated in recent years showing that radiotherapy combined with immunotherapy is more effective than monotherapy alone. Preclinical studies have shown that PD-L1 expression is upregulated on tumor cells after radiotherapy, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. In the clinical setting, patients receiving radiotherapy before anti-PD-1 treatment have had a significantly better prognosis than those who have not undergone radiotherapy. In the present report, we reviewed previous studies of the combination of radiotherapy and anti-PD-1/PD-L1 treatment for NSCLC. In addition, we report our case of a patient whose PD-L1 expression gradually increased in brain metastases from NSCLC after repeated radiotherapy. In the perspectives portion, we focused on the questions of how to integrate radiotherapy into anti-PD-1/PD-L1 agent regimens and described several ongoing clinical trials.     

广泛期小细胞肺癌诱导治疗后胸部放疗序贯PD-1/PD-L1抑制剂的安全性研究

目的:评估胸部放疗序贯联合PD-1/PD-L1抑制剂应用于诱导治疗后的广泛期小细胞肺癌(ES-SCLC)的安全性、耐受性。方法:前瞻性纳入中国医学科学院肿瘤医院1项Ⅰ期临床试验和1项真实世界研究中的ES-SCLC患者,两项研究均经中国医学科学院肿瘤医院伦理委员会批准,选择其中确诊时为广泛期、经系统治疗(化疗/化疗联合P...     

以PD-1/PD-L1为靶点的肺癌免疫治疗临床研究进展

免疫检查点的研究在近几年实现突破性进展,PD-1/PD-L1信号通路与免疫逃逸机制密切相关,针对阻断PD-1/PD-L1 通路免疫检查点的治疗在肺癌中取得明显效果。从Checkmate-017、Checkmate-057研究到KEYNOTE-010研究和OAK研究,逐 步奠定了PD1/PD-L1抑制剂作为化疗失败晚期NSCLC的标准治疗的地位;PD-1/PD-L1抑制剂可联合其他治疗方式,包括放疗、 化疗、靶向治疗以及其他免疫治疗等方式,在肺癌综合治疗中起到协同作用,从而提高了疗效。免疫检查点抑制剂带来了肺癌治 疗模式的改变,也对肿瘤疗效评价模式、治疗相关不良反应的处理带来挑战。另外,免疫检查点抑制剂的研发也有力地推动了精 准医疗的进展。     

程序性死亡蛋白1及其配体在结直肠癌中的临床研究现状

程序性死亡蛋白-1(Programmed cell death protein-1,PD-1)通过与程序性死亡蛋白配体-1(Programmed cell death protein ligand-1,PD-L1)相互作用进而发挥负向调节机体免疫反应机制,促使肿瘤细胞发生免疫逃逸。以PD-1/PD-L1为靶点的免疫治疗已成为肿瘤治疗的新模式。目前,手术和放化疗仍然是结直肠癌的主要治疗手段,但生存率没有明显的改善。研究显示PD-1/PD-L1抑制剂单药治疗或与放化疗和手术联合治疗在结直肠癌中取得了可观的效果,且相关的临床试验正在进行。本文阐述了PD-1/PD-L1信号通路相关的分子生物学机制及PD-L1的表达与结直肠癌放化疗和预后的关系,并介绍了PD-1/PD-L1抑制剂在结直肠癌中的临床研究进展。     

Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms

Despite the unheralded success of immune checkpoint blockade in delivering durable responses for some patients with non-small-cell lung cancer (NSCLC), the majority of patients do not respond. PD-L1 tumour expression and pre-existing tumour T-cell infiltration have been correlated with improved clinical outcomes to anti-PD-1/anti-PD-L1. However, patients with tumours that are negative for PD-L1 expression can also respond to treatment. Strategies to combine other treatment modalities like radiotherapy (RT) with immune checkpoint inhibitors are being investigated as means of improving the response rates to PD-1/PD-L1 antibody blockade. RT induces immunogenic changes in cancer cells, can adaptively upregulate tumour cell PD-L1 expression and can improve the efficacy of anti-PD-1/anti-PD-L1 therapy. How we design future clinical trials in NSCLC also depends on practical considerations of delivering these treatment combinations, such as RT dose, fractionation and field volume, as well as scheduling with immune checkpoint blockade. Here, we review reasons for resistance to anti-PD-1/anti-PD-L1 and how RT may be utilised in combination with these drugs to enhance their effect by building better translational research platforms.     

乳腺癌放疗联合PD-1/PD-L1抑制剂研究进展

放疗可以增强肿瘤特异性免疫反应,同时为免疫药物提供作用靶点,以PD-1/PD-L1为代表的免疫检查点阻断剂联合放疗增强抗肿瘤活性,并且具有远隔效应。本文就放疗联合PD-1/PD-L1抑制剂治疗乳腺癌的基础研究、临床研究进展及面临的挑战做一综述。     

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies

Immune checkpoint antibodies that augment the programmed cell death protein 1 (PD-1)/PD-L1 pathway have demonstrated antitumor activity across multiple malignancies, and gained recent regulatory approval as single-agent therapy for the treatment of metastatic malignant melanoma and nonsmall-cell lung cancer. Knowledge of toxicities associated with PD-1/PD-L1 blockade, as well as effective management algorithms for these toxicities, is pivotal in order to optimize clinical efficacy and safety. In this article, we review selected published and presented clinical studies investigating single-agent anti-PD-1/PD-L1 therapy and trials of combination approaches with other standard anticancer therapies, in multiple tumor types. We summarize the key adverse events reported in these studies and their management algorithms.     

Anti program death-1/anti program death-ligand 1 in digestive cancers

Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between programdeath-1 (PD-1) and program death-ligand 1 (PD-L1) willlead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 mAbs (MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase II will start soon. In metastatic colorectal cancer (CRC), a phase III trial of MPDL3280A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration (i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection of patients likely to benefit from ICIs.