Efficacy and safety comparison of PD-1 inhibitors vs. PD-L1 inhibitors in extensive-stage small-cell lung cancer: a retrospective comparative cohort study

BackgroundEvidence from clinical research and meta-analyses have suggested that programmed cell death 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors plus chemotherapy could achieve a significant survival benefit for extensive-stage small-cell lung cancer (ES-SCLC) patients. However clinical researches concerned about the comparation between the PD-1 and PD-L1 inhibitors were relatively lacking.MethodsWe collected the data of ES-SCLC patients treated with PD-1 inhibitors or PD-L1 inhibitors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoint included adverse events (AEs).ResultsThe data of 221 ES-SCLC patients treated with PD-1 (n=146) or PD-L1 inhibitors (n=75) between February 2017 and June 2020 were retrospectively collected. The median OS (mOS) and median PFS (mPFS) were 19.07 and 8.27 months, respectively, in patients treated with PD-1 inhibitors. In the PD-L1 group, mOS has not been reached, and mPFS was 7.95 months. No significant differences were observed between the 2 groups in OS [hazard ratio (HR), 1.472; 95% confidence interval (CI), 0.847–2.220; P=0.198] and PFS (HR, 0.816; 95% CI, 0.577–1.155; P=0.251). The rates of patients showed AEs of any grade treated with PD-1 or PD-L1 were 67.12% and 64.00%, with no significant difference (P=0.642, χ²=0.216), ≥3 grade AEs occurred in 42 (28.76%) and 16 (21.33%) patients treated with PD-1 and PD-L1 inhibitors separately, also no significant difference (P=0.234, χ²=1.415) was observed. According to subgroup analysis, camrelizumab revealed a longer mPFS (15.17 months) compared with other immune-checkpoint inhibitors (ICIs). PD-1 and PD-L1 inhibitors revealed comparable efficacy in ES-SCLC patients with brain metastases, with no significant differences in OS (HR, 1.505; 95% CI, 0.684–3.311; P=0.309) and PFS (HR, 0.649; 95% CI, 0.356–1.182; P=0.157).ConclusionsPD-1 and PD-L1 inhibitors might achieved comparable survival benefit and safety in ES-SCLC patients. A longer PFS was observed in patients treated with PD-1 inhibitors in the first-line treatment, and the PD-1 inhibitor camrelizumab might have achieved a better PFS compared with other ICIs.     

The efficacy and safety of PD-1/PD-L1 inhibitors versus chemotherapy in patients with previously treated advanced non-small-cell lung cancer: A meta-analysis

Background:Immune checkpoint inhibitor therapy for non-small cell lung cancer is widely used in clinical practice. However, there has not been a systematic statistical proof of the efficacy of PD-1 inhibitors in patients with advanced cancer. This meta-analysis aims to evaluate its efficacy and related influencing factors, so as to provide a basis for clinical diagnosis and treatment.Objective:To assess the effectiveness and safety of programmed death-1 (PD-1)/PD ligand 1 (PD-L1) inhibitors versus chemotherapy as second-line or late-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) via a systematic review of published randomized controlled trials (RCTs).Methods:Studies were identified through PubMed, EMBASE, and Cochrane Library electronic databases. RevMan 5.3.5 was used to analyze the data extracted from all eligible studies.Results:All 4122 eligible patients from 8 RCTs were included in this study. The meta-analysis showed that PD-1/PD-L1 inhibitors could significantly improve overall survival (hazards ratio [HR] 0.71, 95% confidence interval [CI] 0.66–0.77, P < .001), progression-free survival (HR 0.88, 95%CI 0.81–0.94, P = .01), and objective response rate (HR 2.03, 95%CI 1.66–2.49, P < .001) compared with chemotherapy drugs. The incidence of side effects of any grade (HR 0.34, 95%CI 0.29–0.39, P < .001) or grades 3 to 5 (HR 0.15, 95%CI 0.10–0.23, P < .001) consistently showed that PD-1/PD-L1 inhibitors were safer than chemotherapy. Furthermore, subgroup analysis based on tumor proportion score or pathology classification revealed that PD-1/PD-L1 inhibitors significantly improved overall survival compared with chemotherapy.Conclusion:As a second-line or late-line treatment, PD-1/PD-L1 inhibitors are safer and more effective than chemotherapy in patients with advanced NSCLC.     

Comparison of PD-L1 immunohistochemical assays and the significance of PD-L1 expression in thymoma

Thymoma is a relatively rare malignancy, which is categorized as thymic epithelial tumor but known as the most common pathology that is developed in the anterior mediastinum. Complete resection is recommended for localized tumors and usually favorable prognosis can be obtained. However, poor survival period has been reported in unresectable cases exhibiting extensive invasion or distant metastasis, as effective chemotherapeutic regimens are restrained. We previously assessed expression of programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1) and discussed their prospective application in the immunotherapy of thymic epithelial tumors. After our publication, additional studies using reliable PD-L1 antibodies, which are currently administered to predict efficacy of PD-1/PD-L1 blockade therapy were performed and further characterized PD-L1 in thymoma. Herein, recent knowledge in relation to the significance of PD-L1 expression in thymoma is reviewed based on recent findings using qualified PD-L1 clones. Most studies coherently found high expression of PD-L1 on the cell membrane and cytoplasm of tumor epithelial cells in accordance with previous reports, which is a predictive marker for effectiveness of anti-PD-1/PD-L1 drugs, even when approved PD-L1 antibodies were employed. On the other hand, PD-L1 expression on tumor infiltrating immune cells remains to be sufficiently determined. High PD-L1 expression can be expected in cases with high grade histological subtypes, such as type B2/B3 thymomas, or those with advanced stages III or IV of the disease. Interestingly, the level of PD-L1 expression was found to be upregulated after chemotherapy compared with that before, which could be explained by immunogenic cell death. The prognostic impact of PD-L1 expression in thymoma might be found only when thymic carcinoma patients were excluded. Furthermore, it also could be identified when we analyzed thymomas completely resected, distinct from biopsy and incompletely resected cases.     

The current strategy for managing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an inherited autosomal dominant disease presenting with pancreatic neuroendocrine tumors (pNETs), parathyroid tumors, or pituitary tumors. Using the PubMed database, we reviewed the literature on information regarding the proper diagnosis and treatment of MEN1-associated pNET. Many cases of MEN1-associated pNET are functioning pNETs. Gastrinomas and insulinomas tend to occur frequently in the duodenum and pancreas, respectively. In addition to diagnostic imaging, the selective arterial secretagogue injection test (SASI test) is useful for localizing functioning pNET. The standard treatment is surgical resection. However, in the case of a functioning pNET, the tumor should first be accurately located using the SASI test before an appropriate surgical method is selected. In cases of a MEN1-associated non-functioning pNET that exceeds 2 cm in diameter, the incidence of distant metastasis is significantly increased, and surgery is recommended. In cases of unresectable pNET, a somatostatin analog has been shown to demonstrate antitumor effects and is considered to be a promising treatment. In addition, molecular-targeted drugs have recently been found to be effective in phase III clinical trials.     

Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents

Immune checkpoint inhibitors (ICIs) block CTLA‐4, PD‐1 and PD‐L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune‐related toxicities affecting a variety of organs, including the liver. ICI‐associated immune‐mediated hepatitis (IMH) ranges in severity between mild and life‐threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI‐induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre‐existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non‐steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour‐specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune‐related adverse events, would help optimize treatment decisions for individual patients.     

慢性乙型肝炎肝组织中 PD-L1在干扰素治疗中的表达

目的：研究慢性乙型肝炎患者肝组织中程序性死亡分子配体1（PD-L1）在进行聚乙二醇干扰素α-2a 抗病毒治疗前后及不同应答组间的表达变化，以进一步明确其与干扰素抗病毒疗效的相关性。方法15例慢性乙肝患者予以聚乙二醇干扰素α-2a 治疗48周，根据抗病毒疗效分为完全应答组、部分应答组及无应答组，检测治疗前后及不同应答组间 ALT、HBV DNA、HBV 标志物及肝脏病理变化，采用免疫组织化学方法结合图像定量分析系统检测肝组织 PD-L1的表达。结果在长效干扰素抗病毒治疗48周后，完全应答组 ALT 均降至正常，HBV DNA 低于检测下限，HBeAg 出现血清学转换，肝脏炎症程度有所好转，肝脏 PD-L1表达较治疗前明显下降（P ＜0．05）；部分应答组 ALT 降至正常， HBV DNA 较治疗前有所下降，但仍未低于检测下限，HBeAg 未发生血清学转换，肝脏炎症程度有所好转，肝脏 PD-L1表达较治疗前明显下降（P ＜0．05）；无应答组 ALT、HBV DNA、肝脏炎症程度及肝组织 PD-L1的表达较治疗前无明显变化，HBeAg 均未发生血清学转换。结论慢性乙型肝炎患者进行聚乙二醇干扰素α-2a 抗病毒治疗，可通过下调肝组织 PD-L1表达从而抑制病毒复制，改善肝脏炎性反应程度。     

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale,clinical challenges and opportunities

A dynamic interplay exists between host and tumor, and the ability of the tumor to evade immune recognition often determines the clinical course of the disease. Significant enthusiasm currently exists for a new immunotherapeutic strategy: the use of immunomodulatory monoclonal antibodies that directly enhance the function of components of the anti-tumor immune response such as T cells, or block immunologic checkpoints that would otherwise restrain effective anti-tumor immunity. This strategy is based on the evidence that development of cancer is facilitated by the dis-regulation and exploitation of otherwise physiological pathways that, under normal circumstances, down-regulate immune activation and maintain tolerance to self. Among these pathways an important role is covered by the Programmed death-1 (PD-1)/PD-Ligand (L) 1 axis. An emerging concept in cancer immunology is that inhibitory ligands such as PD-L1 are induced in response to immune attack, a mechanism termed “adaptive resistance”. This potential mechanism of immune resistance by tumors suggests that therapy directed at blocking the interaction between PD-1 and PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity. The anti-PD-1 strategy can be effective in several solid tumors such as renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC), however in this review we summarize the biological role of PD-1/PD-L1 on cancer by focusing our attention in the biological rationale, clinical challenges and opportunities to target the PD-1/PD-L1 axis in melanoma.     

Lower expression of PD-1 and PD-L1 in peripheral blood from patients with chronic ITP

Background: T-cell dysregulation is a major event involved in immune thrombocytopenic purpura (ITP). Increasing data have indicated that abnormal expression of T-cell immunosuppressive receptors, such as programmed death (PD) 1 and cytotoxic T lymphocyte antigen-4 (CTLA-4), may be related to autoimmune disease pathogenesis.

Methods: We analyzed the expression levels of PD-1, its ligand PD-L1, and CTLA-4 in peripheral blood mononuclear cells from 18 patients with chronic ITP by real-time polymerase chain reaction, and samples from 20 healthy individuals served as control.

Results: The results demonstrated significantly lower expression of PD-1 (median: 0.0015) and PD-L1 (median: 0.0572) in chronic ITP patients compared with healthy individuals (PD-1: median: 0.0117, P?<?0.0001; PD-L1: median: 0.5428, P?<?0.0001), while there was no significant difference in the CTLA-4 expression level between the chronic ITP patients (median: 0.0818) and healthy individuals (median: 0.1667) (P?=?0.219). Moreover, a positive correlation between the expression levels of PD-1 and PD-L1 (r_s?=?0.486, P?=?0.041) and CTLA-4 and PD-1 (r_s?=?0.643, P?=?0.004) in the chronic ITP patients was found.

Conclusion: Consistently lower expression of T-cell immunosuppressive receptors is a common characteristic of chronic ITP, which may be associated with its pathogenesis.     

PD-L1 expression and surgical outcomes of adenosquamous carcinoma of the pancreas in a single-centre study of 56 lesions

ObjectiveAdenosquamous carcinoma of the pancreas (ASCP) is a rare histologic subtype of pancreatic carcinoma. The clinicopathologic characteristics and surgical outcomes of ASCP are poorly understood due to the rarity of this disease. Recently, promising clinical responses in patients with pancreatic cancer have been obtained for antibodies against programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). This study investigated the prevalence of PD-L1 expression and surgical outcomes of 56 ASCPs compared to 100 pancreatic ductal adenocarcinomas (PDACs).MethodsA total of 56 resected cases of ASCPs were retrospectively reviewed; after matching for the T category, 100 PDACs were selected as a control group for comparison. Immunohistochemistry for p53, Smad4, and PD-L1 was performed in both groups.ResultsThe ASCPs exhibited distinct clinicopathologic features, such as larger tumour, location in the distal pancreas, frequent vascular invasion and distant metastasis. In survival analysis, 1-and 2-year overall survival (OS) rates were 51.8% and 17.9%, respectively, with a median follow-up 13 months. According to multivariate analysis, vascular invasion and T category remained independent predictors of OS. Patients with ASCPs showed poorer survival than patients with PDACs after matching for the T category (p = 0.03). p53 and Smad4 were aberrantly expressed in 42 (75%) and 28 (50%) cases, respectively. Under the condition of a 10% cut-off value for PD-L1 positivity, approximately 11% of ASCPs were positive for PD-L1.ConclusionsApproximately 11% of patients with ASCPs are assumed to be potential candidates for the application of antibodies against PD-1/PD-L1, as based on the immunohistochemical results for PD-L1.     

程序性死亡配体1与肺癌患者临床病理特征及预后关系的Meta分析

目的评价程序性死亡配体1(PD-L1)与肺癌患者临床病理特征及预后的关系。方法计算机检索PubMed、Web of Science,the Cochrane Library、中国生物医学文献数据库(CBM)、中国知网(CNKI)、万方数据知识服务平台及维普网等数据库,检索时间自数据库建立至2019年6月,筛选有关PD-L1与肺癌患者临床病理特征及预后关系的对照研究。采用RevMan 5.3统计学软件进行Meta分析,比较肺癌组织/细胞与正常组织/细胞中PD-L1阳性率,有无淋巴结转移及不同病理类型、不同TNM分期患者肺癌组织/细胞PD-L1阳性率,并比较PD-L1阳性/阴性患者生存率。结果最终纳入9篇文献,包含1863例患者。Meta分析结果显示,肺癌组织/细胞PD-L1阳性率高于正常组织/细胞[OR=13.91,95%CI(3.62,53.38)],有淋巴结转移的患者肺癌组织/细胞PD-L1阳性率高于无淋巴结转移的患者[OR=2.73,95%CI(1.59,4.66)],鳞癌患者肺癌组织/细胞中PD-L1阳性率高于腺癌患者[OR=0.70,95%CI(0.50,0.98)],TNM分期Ⅲ+Ⅳ期患者肺癌组织/细胞PD-L1阳性率高于TNM分期Ⅰ+Ⅱ期患者[OR=2.24,95%CI(1.79,2.81)](P<0.05);PD-L1阳性、阴性患者生存率比较,差异无统计学意义[HR=0.74,95%CI(0.39,1.42),P=0.37]。Egger’s检验结果显示,报道PD-L1阳性、阴性患者生存率的文献无发表偏倚。结论现有文献证据表明,PD-L1与肺癌患者淋巴结转移、病理类型、TNM分期关系密切,但其与肺癌患者预后无明显相关性。     

伴促甲状腺激素瘤的多发性内分泌腺瘤病1型一例报道及文献复习

目的通过研究1例伴有促甲状腺激素瘤的多发性内分泌腺瘤病1型(MEN1)患者的临床诊治过程及结局以提高对本病的认识。方法分析1例伴有促甲状腺激素瘤的MEN1患者诊治过程中的临床表现、生化和激素、影像学、手术及术后病理结果。使用二代测序再以Sanger法验证分析MEN1及其他基因,并以PolyPhen2和PROVEAN在线检测其产物危害性。结果1例19岁的男性患者因高代谢症状和甲状腺激素(THs)升高诊断甲亢,TSH 2.78 mIU/L,TSH受体抗体(TRAb)阴性。并发现高血钙和低血磷、血浆甲状旁腺激素(PTH)升高以及右下甲状旁腺99mTc显影阳性,诊断甲状旁腺腺瘤,手术治疗后上述指标恢复正常。抗甲状腺药物治疗1年症状和激素无明显改变,MRI显示右下垂体大腺瘤,考虑TSH瘤;经鼻蝶入路切除肿瘤后1个月复查TSH和TH恢复正常,免疫组化TSH阳性。CT和MRI发现胰腺体尾部占位,无相关症状。基因分析发现MEN1杂合突变:c.415C>T,p.His139Tyr(H139Y),蛋白质预测为有害。文献复习目前仅有5例报道。结论MEN1中的TSH瘤少见,既需要在甲状腺功能亢进中鉴别出TSH瘤,同时要考虑TSH瘤合并于MEN1,以减少误诊误治。     

Association between preoperative Vasostatin-1 and pathological features of aggressiveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET)

Background

A reliable and accessible biomarker for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) is currently unavailable. Chromogranin A (CgA) represents the best-described neuroendocrine biomarker, but its accuracy is low. Vasostatin-1 (VS-1), a fragment derived from the cleavage of CgA, was recently investigated and found to be more accurate as tumor biomarker in a cohort of patients affected by mainly metastatic small intestinal NET.