免疫检查点抑制剂疗效相关预测模型的研究进展

免疫检查点抑制剂（immune checkpoint inhibitor,ICI）的应用让肿瘤治疗取得了新突破,但不同患者接受免疫治疗后疗效差异较大,仅部分患者能够从中获益。通过检测一些生物标志物可以预测ICI的疗效,如程序性死亡[蛋白]配体-1(programmed death ligand-1,PD-L1)及肿瘤突变负荷（tumor mutation burden,TMB）等。除此之外,目前已有多项研究基于肿瘤患者的基因组学、转录组学或影像组学等数据,筛选多个生物标志物并建立免疫治疗效果相关预测模型。这类模型具备严谨的建立及验证流程,能够纳入更多肿瘤免疫相关变量,有助于提高对ICI疗效的预测能力。本文就肿瘤免疫治疗效果相关预测模型进行综述,以期为免疫治疗获益人群的筛选提供新思路。     

原发性肝癌免疫治疗疗效及预后预测生物标志物的研究现状

原发性肝癌是全球范围内常见的致死性恶性肿瘤，在我国尤其高发。近年来，以程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)抑制剂为代表的免疫治疗已成为原发性肝癌不可或缺的重要治疗手段。免疫治疗在为患者带来生存获益的同时，也面临着不同患者治疗疗效及预后差异大、原发性及继发性耐药、严重免疫相关不良反应等问题，这些问题给临床上免疫联合治疗的应用带来了巨大挑战。在原发性肝癌患者中探索疗效及预后预测生物标志物，筛选免疫治疗优势人群，对于为患者提供个体化治疗方案、改善预后至关重要。目前临床上已有多种预测性生物标志物，本文将就原发性肝癌免疫联合治疗疗效及预后预测相关生物标志物的研究现状及各标志物所面临的临床问题作一综述。     

乳腺癌免疫治疗生物标志物的研究进展

摘 要：免疫检查点抑制剂作为研究的热点已被应用于多种实体瘤中,然而,研究发现部分肿瘤对免疫抑制剂不敏感,同时接受免疫治疗的患者也会出现特殊的、致命的不良反应。研究发现PD?鄄L1、肿瘤突变负荷、微卫星不稳定性以及肿瘤细胞浸润可以预测乳腺癌免疫治疗的反应、评估治疗疗效与预后。骨髓源性抑制细胞、循环肿瘤DNA和LAG3也表现出作为预测标志物的潜力。全文对乳腺癌免疫治疗相关预测生物标志物的最新研究进展作一综述。     

非小细胞肺癌免疫治疗疗效预测的研究进展

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)治疗晚期非小细胞肺癌进入了一个新纪元,但不同于靶向治疗,免疫治疗没有明确的疗效预测因子以指导临床。目前应用较多的是程序性死亡受体配体(programmed cell death ligand 1,PD-L1)表达的检测,然而多项临床试验结果提示只有约20%的NSCLC患者能从中获益。而肿瘤突变负荷(tumor mutation burden,TMB)也逐渐兴起,还有许多检测因子尚在发现中。本综述旨在探讨非小细胞肺癌中免疫治疗的疗效预测因子以更好地指导临床。     

微卫星稳定型结直肠癌免疫检查点抑制剂疗效预测标志物研究进展

寻找微卫星稳定型结直肠癌免疫检查点抑制剂疗效预测标志物能够使更多的患者从免疫治疗中获益。肿瘤突变负荷（TMB）、POLE/POLD1突变、CMS分型、MGMT甲基化等多个指标具有对微卫星稳定型结直肠癌免疫检查点抑制剂疗效进行预测的潜能和价值。本文通过对微卫星稳定型结直肠癌免疫检查点抑制剂疗效预测标志物的相关研究进行综述,以期为寻找微卫星稳定型结直肠癌患者的最佳治疗策略提供参考。     

细胞因子与肿瘤免疫检查点抑制剂治疗相关不良事件关系及临床价值的研究进展

免疫检查点抑制剂(ICI)的应用显著提高了不同类型恶性肿瘤的疗效, 但其引起的免疫治疗相关不良事件(irAE)涉及多个器官和系统, 影响治疗, 威胁患者健康, 甚至危及生命。因此, 需要选择生物标志物来预测、监测irAE的发生, 帮助高风险患者早期诊断, 指导个体化治疗。研究表明, 某些细胞因子参与了irAE的发生、发展。文章就细胞因子与irAE的相关研究进行综述, 为临床预测和监测irAE提供参考。     

从肿瘤免疫微环境角度看免疫治疗疗效预测标志物

尽管免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)在多个肿瘤中观察到持久应答和显著的生存优势,但大多数患者并不能从ICIs治疗中获益。近年来,对ICIs疗效预测生物标志物的鉴定和开发越来越受到重视。肿瘤组织与肿瘤免疫微环境(tumor immune microenvironment,TIME)相依相行,微环境中各种分子和细胞均可与肿瘤发生复杂的相互作用,进而对肿瘤的发生发展及免疫治疗应答产生复杂而多样化的影响。其中,TIME中的免疫和炎症因素对免疫治疗疗效应答具有关键作用。随着高通量测序和微阵列技术的发展,人们对TIME中各组分的了解和认知已逐步深入、全面,同时还开发了基于肿瘤和微环境的ICIs疗效联合预测生物标志物模型。这些突破性研究成果为探索更有效的预测生物标志物开发策略提供了希望,也有助于不同恶性肿瘤患者进行基于ICIs的治疗管理、监测治疗疗效和疾病发展并攻克免疫治疗耐药。本综述从TIME角度出发,概述免疫治疗疗效预测生物标志物研究进展,以及基于肿瘤和免疫微环境因素开发的联合预测模型。     

评估免疫检查点抑制剂治疗非小细胞肺癌预后的生物标志物

免疫检查点抑制剂（ICI）是一种备受关注的肿瘤免疫治疗手段，可通过阻断免疫检查点信号转导来恢复甚至增强T淋巴细胞的抗肿瘤免疫反应以达到抗肿瘤的治疗目的。PD-L1表达水平或可作为派姆单抗的一线使用标准；较高的肿瘤突变负荷（TMB）增加癌细胞抗原表达，使后者易被免疫细胞监视定位并清除，被定义为预测ICI疗效的生物标志物；错配修复基因（MMR）与MSI具有高度一致性，在多种实体瘤中具有预后预测作用；肿瘤浸润淋巴细胞联合TNM分期评估非小细胞肺癌患者预后准确性甚至优于病理标准，通过检测炎症因子的基因表达水平评估T细胞炎症基因表达谱可预测ICI的治疗效果；体细胞突变状态与免疫治疗的预后有关；低水平的中性/淋巴细胞比值（NLR）可能是免疫相关不良事件发生的独立预测因素；肠道微生物通过影响TIL水平干预免疫治疗的效果；除此以外还有其他预测因素可供参考。梳理总结预测相关标志物，分析其价值性与局限性，可为临床选择适合患者的治疗方案，也可使患者临床获益达到最大。     

TMB可预测中国人免疫治疗疗效

<正>免疫检查点抑制剂的兴起大大改变了传统的肿瘤治疗策略,而PD-L1表达及肿瘤突变负荷(tumor mutational burden,TMB)等疗效预测标记物的发现,进一步提高了免疫药物的响应和获益。目前,TMB已被列入美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)最新版指南,但既往研究大多基于高加索人,亚裔人群的TMB分布、疗效预测等问题,均有待更多研究的验证与解答。此外,如何通过探索其它潜在标志物,进一步富集免疫治疗优势人群,也是当前临床的迫切需求。近日,Clinical Cancer Research期刊发表了首个中国肺癌人群免疫药物临床试验大样本研究。该研究由中山大学附     

POLE/POLD1突变在肿瘤免疫治疗预后中的价值

摘 要：免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）已在多种肿瘤中显示出持续的临床疗效。错配修复蛋白缺陷(mismatch repair deficient,dMMR）或微卫星高度不稳定性（microsatellite instability-high,MSI-H）的转移性结直肠癌患者已从免疫治疗中获益。然而,部分PD-L1阴性和微卫星稳定（microsatellite stability,MSS）型结直肠癌患者对免疫治疗也有持续的反应。因此,为了给患者制定最佳治疗方案,选择能够识别免疫检查点阻断疗效的可靠生物标志物,实现精准治疗是至关重要的。DNA聚合酶亚基的关键编码基因POLE/POLD1是除MSI?鄄H和肿瘤突变负荷（tumor mutation burden,TMB）外,最具潜力的免疫治疗预测指标。全文就POLE/POLD1的分子机制及其突变在免疫治疗中的研究进展进行综述。     

Impact of high tumor mutational burden in solid tumors and challenges for biomarker application

Accurate identification of patients with solid tumors likely to respond to immunotherapy is crucial. Tumor mutational burden (TMB) measures the number of somatic mutations in a tumor and is an emerging prognostic and predictive biomarker for anti-programmed cell death (PD) 1/anti-PD-ligand 1 therapy and other immunotherapeutic agents. Tumor mutational burden is assessed optimally by whole exome sequencing, but next generation sequencing provides TMB estimates in a more timely and cost-effective manner. Blood-based measurement of TMB in plasma offers an alternative to the need for adequate tumor tissue for molecular testing, and has demonstrated the ability to identify patients who derive benefit from immunotherapy. Tumor mutational burden has diverse prognostic impact in different solid tumor types and also has a demonstrated role in predicting improved survival in patients receiving immunotherapy. There are challenges to TMB adoption into standard clinical practice, including variations in its definition, with the mutational number defining TMB-high appearing to vary across cancer types. The magnitude of TMB also varies across different tumor types, with the highest levels reported in melanoma and other skin cancers (where ultraviolet light is the dominant mutational process), followed by non-small cell lung cancer and other squamous carcinomas. Concerns regarding inter-laboratory and inter-platform variations in analysis methods have been raised, highlighting the need for standardization. Integration of other genomic or pathological biomarkers with TMB may increase its prognostic and predictive capabilities and validation of individual or combination models in prospective trials is warranted.     

Tumor mutational burden as a predictor of immunotherapy response in breast cancer

Tumor mutational burden (TMB) is a promising tool to help define patients with triple-negative breast cancer (TNBC) most likely to benefit from immune checkpoint blockade (ICB) therapies. Roughly reflecting the degree of neo-antigens that tumors present to immune cells, TMB associates with multiple measures of tumoral immunogenicity and has proven clinically useful in cancers with relatively high mutation burden. TNBC carries higher TMB than other breast cancer subtypes, and recent data suggest that high-TMB TNBC cases may derive particular benefit from ICB in combination with chemotherapy (GeparNuevo, IMpassion130) or even ICB alone (KEYNOTE-119, TAPUR). Given the recent approval of pembrolizumab and atezolizumab in combination with chemotherapy for PD-L1-positive, metastatic TNBC, standardizing TMB calculation methods and cut-off values is of critical importance to deploy this clinical biomarker.     

晚期胃癌一线免疫治疗的现状与进展

晚期胃癌预后较差,传统化疗疗效有限,未能满足患者治疗需求。免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）已改变晚期胃癌治疗格局,其中程序性死亡受体-1(programmed death-1,PD-1)抑制剂联合化疗、PD-1抑制剂联合曲妥珠单抗及化疗已分别成为人表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)阴性或阳性晚期胃癌一线治疗选择,其他免疫检查点分子抑制剂和癌症疫苗、过继性细胞输注等疗法的研究均在进行中。如何通过生物标志物筛选免疫治疗最佳获益人群,是近期研究热点。除肿瘤突变负荷、程序性死亡配体-1(programmed death-ligand 1,PD-L1)表达、微卫星不稳定性等,新兴标志物如循环肿瘤DNA、肠道微生物组学和细胞因子等均值得关注。本文就晚期胃癌一线免疫治疗的临床研究进展及展望进行综述。     

Identification of genomic features associated with immunotherapy response in gastrointestinal cancers

Gastrointestinal (GI) cancers prevail and account for an extremely high number of cancer deaths worldwide. The traditional treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapy, have a limited therapeutic effect for advanced GI cancers. Recently, immunotherapy has shown promise in treating various refractory malignancies, including the GI cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). Thus, immunotherapy could be a promising treatment approach for GI cancers. Unfortunately, only a small proportion of GI cancer patients currently respond to immunotherapy. Therefore, it is important to discover predictive biomarkers for stratifying GI cancer patients response to immunotherapy. Certain genomic features, such as dMMR/MSI, tumor mutation burden (TMB), and tumor aneuploidy have been associated with tumor immunity and im-munotherapy response and may serve as predictive biomarkers for cancer immunotherapy. In this review, we examined the correlations between tumor immunity and three genomic features: dMMR/MSI, TMB, and tumor aneuploidy. We also explored their correlations using The Cancer Genome Atlas data and confirmed that the dMMR/MSI status, high TMB, and low tumor aneuploidy are associated with elevated tumor immunity in GI cancers. To improve the immunotherapeutic potential in GI cancers, more genetic or genomic features associated with tumor immune response need to be identified. Furthermore, it is worth exploring the combination of different immunotherapeutic methods and the combination of immunotherapy with other therapeutic approaches for cancer therapy.     

The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex

Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a fraction of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients more likely to respond to ICI. Here we report that the ICI response prediction biomarker tumor mutational burden (TMB) shows significant sex differences. TMB's predictive power is significantly better for female than for male lung cancer patients. Receiver operating characteristic curve analysis was performed and the area under the curve (AUC) was reported to evaluate the predictive power of TMB in lung cancer ICI response. Hazard ratios (HR) of TMB-high vs. TMB-low patients were compared between male and female patients. Both AUC and HR differences between female and male are significant in all available independent lung cancer datasets. However, the AUC of programmed death ligand 1 (PD-L1) expression does not show a difference between female and male, suggesting TMB, but not PD-L1 expression has a better predictive power for female than for male lung cancer patients. Our study suggests significant sex differences in the performance of TMB in ICI response prediction. Future development of ICI biomarker should consider sex differences and special efforts should be paid to improve the performance of ICI predictive biomarkers for male lung cancer patients.     

驱动基因阴性晚期非小细胞肺癌脑转移免疫微环境及免疫治疗的研究进展

远端转移是晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者难以避免的并发症,脑转移（brain metastases,BM）是此类患者最常见的转移部位之一。脑转移患者可能出现头痛、视物模糊、偏瘫、肢体麻木等症状,生存质量受到严重影响。脑转移患者通常预后较差,自然中位生存期仅有3个月左右。传统上,针对驱动基因阴性NSCLC脑转移的治疗策略有局部干预的外科手术、放射治疗及系统性干预的化疗等,而有明确基因突变如EGFR、ALK、ROS1等的患者可采用新一代靶向药物治疗,但两类患者颅内治疗疗效均欠佳。免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）的出现为晚期肺癌的治疗带来新希望,其在黑色素瘤及肺癌脑转移患者中观察到了一定疗效。脑转移瘤的血管与正常脑血管存在显著差异。不同于肺部原发病灶,脑转移瘤具有独特的肿瘤微环境、免疫细胞特征及血管结构,无论是免疫单药治疗还是免疫联合治疗对肺癌脑转移患者均有效。由于难以获得脑组织样本,免疫治疗的生物标志物的研究受到限制。除了肿瘤细胞程序性死亡-配体1（programmed cell death ligand-1,PD-L1）外,肿瘤突变负荷（tumor mutation burden,TMB）可能是预测免疫治疗疗效的潜在生物标志物。本文梳理脑部肿瘤的微环境特征,回顾ICIs治疗相关研究进展,拟为驱动基因阴性NSCLC脑转移患者的治疗提供参考。      

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

BackgroundTreatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.Materials and methodsIn this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity.ResultsHigh TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established.ConclusionsTMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.     

肿瘤突变负荷在EGFR突变型晚期非小细胞肺癌中的临床研究进展

表皮生长因子受体（epidermal growth factor receptor,EGFR）-酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）的应用使EGFR突变型非小细胞肺癌（non-small cell lung cancer,NSCLC）患者的生存显著改善,但仍有部分患者疗效及预后不佳,寻求预测此类患者疗效及预后的标志物迫在眉睫。肿瘤突变负荷（tumor mutational burden,TMB）前期主要应用于免疫治疗获益人群的筛选及疗效预测,近期在EGFR突变型NSCLC中也有相应的探索性研究。就TMB的检测与挑战及其在EGFR突变型晚期NSCLC中的最新应用研究进展进行综述。