免疫检查点抑制剂治疗小细胞肺癌疗效及预后生物标志物的研究进展

小细胞肺癌（SCLC）的治疗已经迈入免疫治疗时代,免疫疗法联合化疗的一线治疗新标准得以确立。然而并非所有 SCLC患者均能从免疫检查点抑制剂（ICI）中获益,缺乏有效的疗效和患者预后生物标志物在很大程度上限制了其临床应用。目 前,肿瘤相关生物标志物PD-L1表达水平在预测SCLC免疫治疗疗效及患者预后中最为常用;肿瘤突变负荷（TMB）、错配修复缺 陷（dMMR） 和微卫星高度不稳定（MSI-H）也可作为预测 ICI 治疗疗效及患者预后的潜在生物标志物。而 dMMR/MSI-H 因在 SCLC中的发生频率极低,限制了其应用;外周血免疫相关标志物因其便捷性而在SCLC免疫治疗中受到越来越多的关注;肿瘤 微环境相关的生物标志物也有助于识别从ICI治疗中获益的患者。因此,深入了解SCLC的一线免疫治疗现状和预测患者免疫 治疗疗效与预后的潜在生物标志物的研究进展,可为SCLC患者免疫治疗优化策略和分层管理提供思路和参考。     

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。     

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。     

非小细胞肺癌放疗联合免疫治疗的研究进展与挑战

由于部分晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者在免疫治疗后没有产生免疫应答或发生继发性耐药,NSCLC免疫治疗的疗效仍不能令人满意。因此,研究者们开展了多项包括放疗（radiation therapy,RT）联合免疫治疗在内的、致力于增强免疫治疗疗效方法的研究。本研究回顾分析了放疗联合免疫治疗提高NSCLC疗效相关研究的进展,并探索进一步增强这一联合治疗疗效的新途径。首先,我们讨论了目前仅有的两项随机试验（和一项汇总分析）。这些试验表明,免疫治疗联合放疗可提高转移性NSCLC患者的远隔客观缓解率、无进展生存期和总生存期。然后,讨论了与放疗免疫疗效相关的因素和生物标志物,例如低水平的程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)、肿瘤突变负荷（tumor mutational burden,TMB）和患者免疫功能。接下来,我们讨论了放疗逆转免疫治疗耐药的机制和应对措施。最后,讨论了低剂量放疗有助于调控肿瘤间质中抑制T细胞浸润的抑制信号的新作用。综上所述,通过对上述研究的深入分析使更多NSC...     

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。     

Immunotherapy and immunobiomarker in breast cancer: current practice and future perspectives

Among the new cancer cases and resulting deaths among women worldwide, breast cancer is the most significant threat to women’s health. In recent years, immunotherapy was initially used to treat patients with metastatic breast cancer, where it demonstrated its unique value by providing a novel way to improve therapeutic effects and prolong survival time. With the development of clinical trials related to immunotherapy for breast cancer, tumour vaccines, such as DNA vaccines, have been observed to improve the disease-free survival (DFS) and overall survival (OS) of patients. Monoclonal antibodies have also shown good efficacy, and adoptive cell therapies, such as CAR-T, exhibit strong tumour killing ability and good safety, and thus, these therapies may comprise a new strategy for the treatment of breast cancer. These breakthrough successes have promoted the achievement of “individualized” breast cancer treatment. Moreover, a recent study showed that patients with various cancer types with a higher tumour mutational burden (TMB) are more likely to benefit from immunotherapy. As research progresses, TMB may also demonstrate a certain clinical significance in the treatment of breast cancer. This paper reviews the latest research progress on breast cancer immunotherapy and the predictive value and application status of TMB in immunotherapy regimens for breast cancer patients to provide a reference for further in-depth studies of breast cancer immunotherapy.     

Pembrolizumab and Trastuzumab in High Tumor Mutational Burden and POLE-Mutated HER2-Positive Refractory Breast Cancer

Metastatic breast cancer (mBC) is an incurable disease, and it is not sensitive to immunotherapy due to its low immunogenicity. Recently, inactivated DNA polymerase epsilon (POLE) mutations have been found to be associated with high tumor mutational burden (TMB), which is an effective immuno-oncology biomarker. Patients with POLE mutations with different types of cancer have properly responded to immunotherapy. We aimed to report the first case of programmed death-ligand 1 (PD-L1)-negative mBC presenting with high TMB and POLE mutations, in which a complete response to 5 cycles of chemotherapy and 1 year of pembrolizumab and trastuzumab was noted after failing several lines of HER2-targeted therapies. Our findings also suggest that biomarker-driven patient selection is highly significant for further clinical development of combination therapies via anti-HER2 plus immune-checkpoint inhibitors for HER2+ BC patients.     

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.     

Complete and Durable Response to Nivolumab in Recurrent Poorly Differentiated Pancreatic Neuroendocrine Carcinoma with High Tumor Mutational Burden

Poorly differentiated pancreatic neuroendocrine carcinomas (NECs) are rare and aggressive malignancies with rapid disease progression and early widespread metastasis. Given histology similarity, they are commonly treated with platinum-based chemotherapy as small cell lung cancer (SCLC). However, no standard treatment has been established for recurrent or progressive disease. We present an Asian patient with recurrent poorly differentiated pancreatic NEC after curative surgery and adjuvant chemotherapy with cisplatin and etoposide. The tumor mutational burden (TMB) was high. The patient received chemotherapy combined with maintenance immunotherapy with nivolumab and achieved promising and durable response, suggesting TMB could be a biomarker to identify NEC patients for immune checkpoint inhibitor (ICI) treatment.     

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.