肿瘤免疫检查点抑制剂相关肺炎的管理

以免疫检查点程序性死亡因子-1（programmed death 1，PD-1）抑制剂、程序性死亡因子配体-1（programmed death ligand 1，PD-L1）抑制剂及细胞毒性T淋巴细胞相关蛋白4（cytotoxic T lymphocyte antigen 4，CTLA-4）抑制剂为代表的肿瘤免疫治疗，近年来在肿瘤治疗中广泛开展，有效延长了肿瘤患者的生存期，但也可能导致免疫治疗相关不良事件（immune-related adverse events，irAEs）。免疫检查点抑制剂（immune checkpoint inhibitor，ICIs）相关肺炎是常见的irAEs之一，可导致部分肿瘤患者治疗暂停、治疗失败、甚至威胁生命。正确了解ICIs相关肺炎的临床特点，早期诊断并恰当治疗，对影响肿瘤患者的预后、延长生命有重要意义。     

细胞程序性死亡受体-1/细胞程序性死亡配体-1抑制剂相关内分泌不良反应及处理现状

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)开始用于治疗多种癌症,疗效显著.细胞程序性死亡受体-1 (programmed death 1,PD-1)抑制剂和细胞程序性死亡配体-1 (programmed cell death-ligand 1,PD-L1)抑制剂都是临...     

免疫检查点抑制剂相关心肌炎分子机制研究进展

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已成为目前应用最广的恶性肿瘤免疫疗法，主要包括CTLA-4（cytotoxic T lymphocyte associated antigen-4）抑制剂、PD-1/PD-L1（programmed death protein-1/ligand-1）抑制剂和LAG-3（lymphocyte activation gene-3）抑制剂。ICIs导致的最致命的免疫相关不良反应（immune-related adverse events, irAE）之一为免疫检查点抑制剂相关的心肌炎（immune checkpoint inhibitor-associated myocarditis, ICIAM）。ICIs联合治疗时ICIAM的发病率多高于单药治疗。其分子机制主要包括免疫检查点作为新抗原、肿瘤同源抗原的异位识别、免疫检查点心脏保护的阻断、自身抗体和炎症因子的产生以及微生物的调节作用等。目前已有多种治疗ICIAM药物及非药物性方案。对于ICIAM分子机制的探索和治疗管理方案的进步仍需多学科共同努力。     

免疫检查点抑制剂的内分泌毒性及临床应对策略

以细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)和免疫检查点程序性死亡蛋白1(programmed cell death protein 1,PD-1)/程序性死亡分子配体1(programmed death-ligand 1,PD-...     

免疫检查点抑制剂致肺部不良反应的诊治进展

正免疫检查点抑制剂(immune checkpoint inhibitor,ICI)是针对机体免疫检查点的单克隆抗体。目前常用的ICI有程序性死亡受体1(programmed cell death protein 1,PD-1)抑制剂[纳武利尤单抗(nivolumab)、帕博利珠单抗(pembrolizumab)]、程序性死亡配体1 (programmed death-ligand 1,PD-L1)抑制剂[阿替利珠单抗(atezolizumab)、度伐利尤单抗(durvalumab)]及细胞毒T细胞抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂[伊匹木单抗(ipilimumab)和曲美木单抗(tremelimumab)]。ICI已被批准用于治疗黑素瘤、肾细胞癌、     

免疫检查点抑制剂不良反应的研究进展

正癌症的诊断及治疗策略。免疫检查点抑制剂通过阻断免疫内在的负性因子如细胞毒性T淋巴细胞相关抗原4 (cytotoxic T lymphocyte-associated antigen 4,CTLA-4),程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡配体-1(programmed death-ligand 1,PD-L1)来增强抗肿瘤免疫[1]。PD-1抑制剂如nivolumab和pembrolizumab,以及PD-L1抑制剂如avelumab、durvalumab和atezolizumab已被开发,并已获得美国FDA和欧洲药物管理局(European Drug Administration,EMA)的批准[2]。CTLA-4主要参与淋巴结内T细     

靶向免疫负调控的药物在血液肿瘤中的应用及前景

传统的化学治疗对白血病的治疗效果越来越局限,目前有许多靶向免疫负调控药物及其相关的抗体研究,以求在血液病治疗上取得突破性进展。近几年,如细胞毒性T淋巴细胞抗原 4（cytotoxic T lymphocyte antigen 4,CTLA 4）、程序性死亡受体 1（programmed death receptor 1,PD L1）及中药等负性免疫调控因素受到广泛关注。本文就靶向免疫负调控药物在血液病中的应用及前景做一综述。     

免疫检查点抑制剂血液系统不良事件

<正>免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)包括程序性死亡受体-1 (programmed death-1,PD-1)单抗、程序性死亡受体-配体1 (programmed death-ligand 1,PD-L1)单抗和细胞毒性T淋巴细胞相关抗原-4(cytotoxic T-lymphocyte-associated protein-4,CTLA-4)单抗等,是通过抑制或阻断CTLA-4或PD-1等信号通路重新激活T淋巴细胞来识别癌细胞,从而达到抗肿瘤作用。随着ICIs的广泛应用,免疫治疗所致免疫耐受失衡导致免疫相关不良事件(immune-related adverse events,irAEs)得到关注及重视,内分泌器官、免疫系统器官、皮肤、肺、胃肠道相关不良事件较为常见,而血液系统不良事件的报告相对较少。对9324例使用ICIs的患者进行meta分析显示,贫血、中性粒细胞减少和血小板减少的发生率分别为9.8%、0.94%和2.8%^[1]。     

外周血免疫细胞对PD-1单抗治疗晚期膀胱尿路上皮癌疗效的预测作用

目的 探索晚期膀胱尿路上皮癌（urothelial bladder cancer, UBC）患者外周血免疫细胞数量对程序性死亡蛋白-1 (programmed cell death protein 1, PD-1)单抗治疗的疗效预测作用。方法 我们回顾性分析了我院86例接受PD-1单抗治疗的晚期UBC患者。收集患者临床信息，外周血免疫细胞数据及肿瘤组织PD-1/程序性死亡配体1(programmed cell death ligand 1, PD-L1)表达情况，并分析这些指标与患者生存及对PD-1单抗治疗客观反应率(objective response rate, ORR)的影响。结果 患者TNM分期早（P=0.02），外周血NK细胞数量高（P=0.009），CD4+T细胞占总T细胞比例高（CD4+T%，P=0.009）及B淋巴细胞数量高（P=0.038）是患者总体生存期（overall survival, OS）良好的独立预后因子。患者TNM分期早（P＜0.001），外周血NK细胞高（P=0.043）及B淋巴细胞高（P=0.027）是患者无进展生存期（progression free survival, PFS）良好的独立预后因子。外周血B淋巴细胞数量高（P=0.011），CD4+T比例高（P=0.041）和总淋巴细胞数量高（P＜0.001）的患者对PD-1单抗治疗有更高的ORR。结论 本研究发现患者外周血NK细胞，B淋巴细胞及CD4+T细胞可能在晚期UBC抗肿瘤免疫中发挥重要作用。患者外周血B淋巴细胞数量，CD4+T%和总淋巴细胞数量影响患者对PD-1单抗治疗的ORR，可能参与PD-1单抗疗效发挥的进程。     

B和T淋巴细胞弱化因子在感染性疾病中的免疫作用

B和T淋巴细胞弱化因子(B and T lymphocyte attenuator,BTLA)是继程序性死亡因子-1(programmed death-1,PD-1)、细胞毒性T细胞活化抗原4(cytotoxic T lymphocyte Antigen-4,CTLA-4)后发现的第三个属于CD28免疫球蛋白超家族的负性共刺激分子,抑制或下调T细胞的活化和细胞因子的产生。BTLA参与不同感染性疾病的发生和发展。本文根据国内外的研究进展,对BTLA在感染过程中的免疫作用做简要综述。     

Immune checkpoint inhibitor-induced colitis:A comprehensive review

Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1.ICIs have revolutionized the treatment of a variety of malignancies. However,many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis(IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease,however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.     

CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma

The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti–PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor–associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.     

The potential combinational immunotherapiesfor treatment of hepatocellular carcinoma

The treatment choices available for hepatocellular carcinoma (HCC) are limited and unsatisfactory. Recent improvements in our understanding of the mechanism involving immune checkpoints, including programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and also progress in the development of medicines make immunotherapy a promising approach to the treatment of numerous cancers, especially HCC. However, around 40% of patients still suffer from a progressive disease when treated with a monotherapy. Several clinical trials applying a combination therapy including immune checkpoint inhibitors have demonstrated the durable antitumor activity of these approaches in HCC patients. These clinical trials were done with the intent of evaluating the safety of these combination therapies, as well as whether they help improve the overall survival of patients. This study reviewed the recent progress in the use of combination therapies including immunotherapy in treating patients with HCC.     

Immune checkpoint inhibitors in gynecologic cancers with lessons learned from non-gynecologic cancers

ABSTRACT

Introduction: The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune response against recurring cancer cells leading to long-term remissions for cancer patients. The use of immune checkpoint inhibitors, which work by targeting molecules that regulate immune responses, might be a promising avenue of immunotherapeutic research in gynecologic cancers.

Areas covered: This review focuses on the use of immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and the programmed death receptors such as PD-1 and PD1-ligand in gynecologic cancers. Combinatorial approaches utilizing immunotherapeutic agents with conventional treatments as well as immune-related response criteria and the adverse effects arising due to checkpoint inhibitor immunotherapy have been also discussed in the review.

Expert opinion: After years of very little success, a better understanding of the pivotal role of the tumor microenvironment in suppressing anticancer immunity and the exploration of treatment regimens using immune checkpoint inhibitors alone or in combination have finally led to the development of effective cancer immunotherapies and to improve survival of patients with certain types of advanced cancers. While the clinical experience with immune checkpoint inhibitors in gynecologic cancer patients remains limited, early signal of clinical activity strongly suggest that immunotherapy will play a significant role in the year to come in at least a subset of gynecologic cancer patients.     

Immune checkpoint inhibitor–associated myocarditis: manifestations and mechanisms

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.     

Dramatic response to immunotherapy in an epidermal growth factor receptor-mutant non-small cell lung cancer: A case report

BACKGROUNDThe advent of immune checkpoint inhibitors (ICIs) has revolutionized the management of several types of solid cancers, including lung cancer, by boosting the body''s natural tumor killing response. However, it is undeniable that only a small proportion of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can achieve long-term responses and benefit from immunotherapy.CASE SUMMARYHerein, we report the case of a 48-year-old man diagnosed with stage IV lung adenocarcinoma with an EGFR L858R mutation who was administered pembrolizumab monotherapy followed by pemetrexed and achieved a 10-month progression-free survival interval. In this case report, we show that ICIs were effective for our patient with EGFR-mutated NSCLC and discuss the characteristics of patients who can benefit from immunotherapy.CONCLUSIONWe suggest that patients with EGFR-mutated NSCLC with high PD-L1 expression (defined as ≥ 25%), the L858R mutation, smoking history, or pemetrexed pretreatment may benefit from immunotherapy.     

Evaluation of the immune checkpoint factors in idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN), a single-organ autoimmune disease, is recognized by autoantibodies to podocyte proteins and identified as the most frequent cause of nephrotic syndrome in adults. T cells are important contributors in autoimmunity since they promote B–cell development, antibody production, direct inflammation, and organ tissue cytotoxicity. This study investigated the inhibitory immune checkpoint (ICP) receptors expressed on T lymphocytes and other immune cells. Thus, PBMCs from IMN patients were obtained before treatment, and the levels of ICPs such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin-3 (TIM-3) were examined at both gene and protein expression using real time PCR and Western blot tests respectively. The results illustrated that gene expression levels of ICPs reduced significantly in comparison to the control which were verified by related fold changes of protein expression sequentially. Our study revealed that CTLA-4, PD-1, TIM-3, and LAG-3 expression is impaired in IMN patients before treatment which could be a potential target for therapy.     

Non–Small Cell Lung Cancer: Epidemiology,Screening, Diagnosis,and Treatment

Lung cancer remains the leading cause of cancer deaths in the United States. In the past decade, significant advances have been made in the science of non–small cell lung cancer (NSCLC). Screening has been introduced with the goal of early detection. The National Lung Screening Trial found a lung cancer mortality benefit of 20% and a 6.7% decrease in all-cause mortality with the use of low-dose chest computed tomography in high-risk individuals. The treatment of lung cancer has also evolved with the introduction of several lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations. Similarly, immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of NSCLC treatment. Furthermore, the results of new trials continue to help us understand the role of these novel agents and which patients are more likely to benefit; ICIs are now part of the first-line NSCLC treatment armamentarium as monotherapy, combined with chemotherapy, or after definite chemoradiotherapy in patients with stage III unresectable NSCLC. Expression of programmed cell death protein-ligand 1 in malignant cells has been studied as a potential biomarker for response to ICIs. However, important drawbacks exist that limit its discriminatory potential. Identification of accurate predictive biomarkers beyond programmed cell death protein-ligand 1 expression remains essential to select the most appropriate candidates for ICI therapy. Many questions remain unanswered regarding the proper sequence and combinations of these new agents; however, the field is moving rapidly, and the overall direction is optimistic.