晚期非小细胞肺癌免疫治疗现状及未来方向

肺癌仍然是中国发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌（non-small cell lung cancer,NSCLC）约占80%以上。以靶向程序性死亡[蛋白]-1（programmed death protein-1,PD-1）或程序性死亡[蛋白]配体-1（programmed death ligand-1,PD-L1）的免疫检查点抑制剂（immune checkpoint inhibitor,ICI）为基础的治疗已成为了晚期肺癌的标准治疗手段之一。本综述将对晚期NSCLC免疫治疗的现状予以梳理,探讨现阶段面临的问题与挑战,并思考与展望未来发展方向。     

非小细胞肺癌免疫检查点抑制剂相关性肺炎研究进展

摘 要：免疫检查点抑制剂主要包括细胞毒性T淋巴细胞抗原4（CTLA-4）抗体和程序性细胞死亡蛋白-1（PD-1）及配体（PD-L1）单克隆抗体,在非小细胞肺癌治疗中表现出良好疗效。免疫检查点抑制剂相关性肺炎（checkpoint inhibitor-related pneumonitis,CIP）临床发生率低,但易造成免疫治疗延迟或终止,严重可导致死亡。接受免疫检查点抑制剂治疗后出现新发呼吸道症状的患者必须高度怀疑肺炎。该综述简要介绍了CIP的流行病学、机制和临床特点等,并讨论CIP的治疗策略。     

PD-L1高表达晚期非小细胞肺癌患者单纯免疫治疗与免疫联合化疗疗效比较

背景 与目的以免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)为代表的免疫治疗越来越广泛地应用于肺癌治疗.然而,对于程序性死亡受体配体1(programmed cell death-ligand 1,PD-L1)高表达,即肿瘤比例评分(tumor proportion score,...     

非小细胞肺癌的联合免疫治疗现状

对于晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的患者来说,化疗、放疗、靶向治疗及抗血管生成治疗虽然可以改善其预后,但经相关研究发现,NSCLC患者的5年生存率仍不尽人意。近年来以程序性死亡蛋白1（programmed cell death protein 1,PD-1）/程序性死亡蛋白配体1（programmed death-ligand 1,PD-L1）抑制剂为代表免疫检查点抑制剂的出现为晚期NSCLC患者的治疗带来了新的希望。探索免疫检查点抑制剂联合化疗、抗血管生成药物、放疗的各项治疗策略是目前肿瘤界的热门话题,本文将对NSCLC联合免疫治疗的现状进行总结与讨论。     

免疫抑制剂治疗肺癌同时出现肿瘤超进展和免疫相关性肺炎1例报道并文献复习

<正>近年来,随着免疫治疗在黑色素瘤、肾癌、非小细胞肺癌(non-small cell lung cancer, NSCLC)中的广泛应用,免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)受到越来越多的关注,ICIs广泛应用于驱动基因阴性的晚期NSCLC的一线治疗。ICIs包括程序性细胞死亡蛋白1(programmed cell death protein-1,PD-1)抑制剂、     

PD-1抑制剂治疗致眼睑下垂伴免疫相关性肌炎1例分析北大核心

近年来,随着医学的发展和临床实践的积累,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一种新型的抗肿瘤药物在晚期恶性肿瘤治疗中取得了一定的疗效。程序性死亡受体-1(programmed death protein-1,PD-1)抗体是免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)常见的代表性药物,因其能增强免疫细胞活性,抑制肿瘤细胞的免疫逃逸,在临床肿瘤治疗领域广泛应用[1-2]。     

PD-1信号通路在非小细胞肺癌中的研究进展

免疫治疗是目前除手术、化疗、放疗及靶向治疗外,另一种能够有效改善肺癌预后的治疗方法。在各种免疫治疗方法中,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)在近年来发展迅速,已成为肿瘤治疗领域的新兴疗法及研究热点。其中,程序性死亡受体1(programmed death receptor 1,PD 1)及其配体程序性死亡配体 1(programmed death receptor ligand1,PD L1)的抑制剂在多种恶性肿瘤的治疗中均取得了显著疗效,部分药物已被美国FDA批准应用于临床。该文对PD 1／PD L1抑制剂在晚期非小细胞肺癌(non small cell lung cancer,NSCLC)患者治疗中的临床研究现状进行综述,探讨其在晚期NSCLC治疗中的临床应用价值、前景及面临的问题与挑战。     

病理学指导下的非小细胞肺癌个体化免疫治疗

在肺癌个体化免疫治疗时代，如何有效地筛选程序性死亡［蛋白］-1（programmed death-1，PD-1）/程序性死亡［蛋白］配体-1（programmed death ligand-1，PD-L1）免疫检查点抑制剂潜在获益人群成为免疫治疗时代面临的新挑战。病理科医师通过免疫组织化学检测非小细胞肺癌（non-small cell lung cancer，NSCLC）组织中PD-L1的表达水平，可为预测PD-1/PD-L1免疫检查点抑制剂治疗晚期NSCLC的疗效和预后提供准确可靠的依据。此外，病理科医师可通过传统病理学方法观察主要病理学缓解（major pathological response，MPR）程度，进一步评价早中期肺癌免疫新辅助治疗的效果。对目前病理学诊断指导下的NSCLC个体化免疫治疗的进展以及未来的发展方向进行综述。     

免疫检查点抑制剂的疗效预测标志物

针对程序性死亡受体1(programmed death receptor 1,PD-1)/程序性死亡受体配体1(programmed death receptor ligand 1,PD-L1)通路的免疫检查点抑制剂（immune checkpoint inhibitors,ICI）的研究十分热门,为多种晚期肿瘤患者的治疗提供了新的希望。然而,ICI的有效率仍偏低,非目标患者对其没有应答,部分患者会出现延迟反应、假性进展等特殊应答模式,目前尚无精准的疗效预测标志物能够提前对患者的肿瘤反应及预后做出判断,使得患者在应用免疫检查点抑制剂时受到限制,本文对目前常用及部分近期研究的疗效预测标志物进行简要综述。     

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。     

非小细胞肺癌患者免疫检查点抑制剂相关性肺炎与免疫检查点抑制剂疗效相关性分析

目的：探讨免疫检查点抑制剂（ICI）治疗非小细胞肺癌（NSCLC）患者发生免疫检查点抑制剂相关性肺炎（CIP）的发生情况和免疫治疗疗效的关系，分析接受ICI 治疗的NSCLC患者的预后相关因素。方法：回顾性分析2020 年3月至2023 年3月在新疆医科大学附属肿瘤医院接受ICI 治疗145 例NSCLC患者的临床资料，将患者分为CIP 组和非CIP 组，随后将发生CIP 的患者分为轻度（1、2级）CIP 和重度（3、4级）CIP 两个亚组，通过Kaplan-Meier 法比较生存曲线，分析CIP 的发生及严重程度对于患者PFS 及OS的影响。通过单因素及多因素COX风险比例回归模型分析与PFS 和OS相关的预后因素。结果：145 例患者中有26例患者出现CIP，发生率为17.93％，重度CIP 发生率为3.45%。CIP 组患者PFS 明显长于非CIP 组患者（12.3 vs 7.6个月，P<0.05），CIP 组与非CIP 组的OS比较差异无统计学意义（16.2 vs 15.8个月，P>0.05)。亚组分析显示，轻度CIP 和重度CIP 相比，PFS（12.2vs 12.9 个月）及OS（16.1 vs 17.8 个月）均无统计学意义（均P>0.05）。多因素COX 回归分析显示，CIP[HR=0.55，95%CI（0.33,0.90），P=0.02]、免疫疗程>6 个[HR=0.51 ，95%CI（0.31, 0.85），P=0.01]是影响患者PFS 的有利预后因素，免疫疗程>6 个[HR=0.4，95%CI（0.18, 0.88），P=0.02]是影响OS的有利预后因素。结论：CIP 的发生率为17.93％，CIP 的发生与PFS 的延长密切相关。免疫疗程>6个是影响NSCLC患者PFS、OS的有利预后因素。     

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer

PurposeThe combination of an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody with platinum-based chemotherapy can improve outcomes for patients with advanced non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) compared with chemotherapy alone. For patients receiving these new treatment regimens, it is important that toxicities be managed effectively. A particular challenge can be determining the etiology of an event, especially when there are overlapping symptoms that can be attributed to either immunotherapy or to platinum-based chemotherapy. Here, we evaluate adverse events (AEs) reported in clinical trials of combination therapy with an anti-PD-1 or anti-PD-L1 (anti-PD-[L]1) immunotherapy and chemotherapy to provide information on toxicity management.MethodsWe performed a systematic review of the literature focused on randomized controlled trials of anti-PD-(L)1 therapy combined with platinum-based chemotherapy for advanced/metastatic NSCLC and SCLC.ResultsEleven reports from 9 randomized studies evaluating pembrolizumab, nivolumab, and atezolizumab combined with platinum-based chemotherapy in patients with advanced lung cancer were identified. Immune-mediated AEs and infusion reactions occurred more commonly in patients who received anti-PD-(L)1 immunotherapy with platinum-based chemotherapy compared with chemotherapy alone; however, there was no evidence of unexpected or unanticipated toxicity with these combinations.ConclusionCombinations of anti-PD-(L)1 immunotherapy with platinum-based chemotherapy regimens improve outcomes for patients with NSCLC and SCLC, and toxicity is generally manageable. Strategies for appropriate workup of AEs to allow clinicians to make informed decisions regarding causality and treatment modifications when appropriate are an important element of management of patients receiving an anti-PD-(L)1 agent combined with platinum-based chemotherapy.     

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

Colorectal cancer (CRC) represents the third cause of cancer-related mortalities worldwide. The progression of CRC to the metastatic phase significantly compromises the overall survival rates. Despite the advances in the therapeutic protocols, CRC treatment is still challenging. Cancer immunotherapy joined the ranks of surgery, chemotherapy, radiotherapy and targeted therapy as the fifth pillar in the foundation of cancer therapeutics. Interruption of the immunosuppressive signals within the tumor microenvironment and reactivation of antitumor immunity via targeting the molecular immune checkpoints generated promising therapeutic outcomes in several types of hard-to-treat cancers. The year 2017 witnessed the first US Food and Drug Administration (FDA) approval of immune checkpoint inhibitor (ICI) immunotherapy for the management of CRC. The approval was granted to pembrolizumab (anti-PD-1) for the treatment of patients with advanced/metastatic solid malignancies with mismatch-repair deficiency including CRCs. Such natively immunogenic tumors constitute only a minor percentage of all CRCs. Therefore, it is imperative to utilize novel combinatorial regimens to enhance the response of a wider range of CRC tumors to cancer immunotherapy and help in extending the survival rates in patients with advanced/metastatic disease. This review highlights the novel approaches under clinical development to overcome the resistance of CRCs to immunotherapy and improve the therapeutic outcomes.     

Pneumonitis in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors

Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti–programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial-enrolled and non–trial-enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti–programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%–5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy.     

治疗后嗜酸性粒细胞水平评价预测PD-1单抗治疗胰腺癌患者疗效和预后的价值（附2例）

目的:观察PD-1单抗治疗后长期持续获益的晚期胰腺癌患者外周血嗜酸性粒细胞水平的变化。方法:分析我院2例应用PD-1单抗治疗后长期持续获益的晚期胰腺癌患者的临床资料,探究在治疗过程中嗜酸性粒细胞水平的变化与疗效之间的关系。结果:2例晚期胰腺癌患者采用PD-1单抗治疗后肿瘤病灶均显著缩小,无进展生存期均明显延长,疗效持续时间已分别大于25个月和15个月,治疗期间定期复查发现外周血嗜酸性粒细胞计数及比率较基线均有明显升高,尤其是治疗半年后增高特别显著,且均未出现免疫相关不良反应。结论:嗜酸性粒细胞水平可能是PD-1单抗治疗胰腺癌长期获益的潜在评价指标,治疗过程中嗜酸性粒细胞显著增多提示免疫获益时间长,对于临床疗效评价和预后判断具有一定的预测价值。     

Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma

With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single-agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment-related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity.     

PD-1/PD-L1抑制剂在结直肠癌治疗中的现状及预后预测

结直肠癌(colorectal cancer,CRC)死亡率在世界范围内居第4位,是癌症相关死亡的一个重要原因,严重威胁患者的生存及生活质量。手术、化疗和放疗是CRC的主要治疗手段,但CRC患者的总生存率却没有显著提高,亟待寻找新的治疗手段。肿瘤免疫逃逸在肿瘤增殖、复发和转移过程中发挥着关键作用。免疫检查点程序性死亡受体1(programmed death-1,PD-1)及其配体1(programmed death-ligand1,PD-L1)在肿瘤免疫逃逸中发挥着重要作用,抗PD-1/PD-L1治疗在癌症治疗中成为研究热点。越来越多的研究提示,抗PD-1/PD-L1免疫治疗在微卫星高度不稳定(microsatellite instability-high,MSI-H)CRC治疗中已取得显著疗效。因此,本研究就抗PD-1/PD-L1疗法在CRC患者中的临床应用,以及改善其低反应率的各种策略进行了总结,并对肿瘤细胞表面PD-L1表达水平在CRC预后中的预测价值进行综述。     

抗PD-1抗体联合治疗晚期肝细胞癌的真实世界研究

目的探讨真实世界中以抗PD-1抗体为基础的疗法在晚期肝细胞癌治疗中的疗效、不良反应及可能影响疗效的因素。方法收集55例接受以PD-1抗体为基础治疗的晚期肝细胞癌患者,回顾性分析其临床特点、疗效及不良反应,并进行随访。结果客观有效率为21.8%,疾病控制率为76.4%。治疗过程中不良反应整体发生率为81.8%,其中3~4级不良反应发生率为14.5%,免疫相关不良反应发生率为58.2%,其中3~4级免疫相关不良反应发生率为3.6%,无治疗相关死亡。55例患者中位无进展生存期为5.0月(95%CI:3.9~6.1),中位生存期11.4月(95%CI:6.5~16.3)。应用抗PD-1抗体前患者肝功能Child-Pugh评分和体能状态ECOG评分是影响治疗有效率和生存时间的主要因素;多因素分析也表明治疗前患者的体能状态ECOG评分和肝功能Child-Pugh评分是影响患者生存的独立预后因素(P<0.001,P=0.034)。结论真实世界中以PD-1抗体为基础的治疗在晚期肝细胞肝癌患者中是安全有效的,其中治疗前患者的体能状态ECOG评分和肝功能Child-Pugh评分是影响患者生存期的独立预后因素。     

免疫检查点抑制剂相关性肺炎的临床观察及文献复习

目的:观察免疫检查点抑制剂相关性肺炎（checkpoint inhibitor pneumonitis,CIP）的发生率、症状及影像学表现，并探索其危险因素。方法:回顾性分析2018年03月至2020年12月在青岛市市立医院接受免疫治疗的60例患者的临床资料，总结CIP的发生率，观察其临床症状和影像学征象，并对CIP患病组和未患病组的临床资料进行统计学分析，探索影响CIP发生的危险因素。结果:60例患者中，5例发生CIP（3例G1，1例G2，1例G4），发生率8.3%，1例死亡，死亡率1.7%。CIP发生中位时间2.1个月（2~9个月）。临床症状主要包括呼吸困难、咳嗽、发热和胸痛。影像学表现各异，共同点是多个病例出现磨玻璃密度影、小叶间隔增厚，分布区域位于支气管血管束周围或胸膜下区。 合并肺部基础疾病可能为CIP发生的危险因素。结论:免疫检查点抑制剂相关性肺炎发生率较低，临床症状及影像学征象无特异性，无明确诊断标准。目前临床诊治经验少，严重者可危及生命，早发现、早诊断、早干预至关重要。