免疫检查点抑制剂相关毒性的机制及其治疗的研究进展

免疫检查点抑制剂在肿瘤治疗中的地位日益突出,显著延长肿瘤患者的生存时间。其关键机制是特异性结合PD-1/PD-L1或CTLA-4靶点,破坏肿瘤免疫耐受,激活淋巴细胞和免疫细胞从而杀灭肿瘤细胞。然而,免疫检查点抑制剂相关毒性的机制还尚未完全明了,故了解其机制并早诊断和早治疗仍是降低毒副反应发生的重要措施。本文对免疫检查点抑制剂相关毒性的机制和治疗的研究进展进行综述。     

免疫检查点抑制剂心脏毒性的临床热点与争议

免疫检查点抑制剂(ICIs)使多种晚期恶性肿瘤的治疗模式开启了新变革。尽管免疫检查点抑制剂相关心脏毒性较为罕见,但致死性极高。以往研究中免疫检查点抑制剂心脏毒性的发生率被低估。本综述聚焦于目前免疫检查点抑制剂心脏毒性方面的研究进展,包括流行病学、评估、诊断、治疗和预后等。接受ICIs治疗者的最佳肿瘤心脏病管理模式仍面临诸多挑战。     

免疫检查点抑制剂所致肝脏不良反应的研究进展

免疫检查点抑制剂通过阻断T淋巴细胞负性调控信号以达到增强T淋巴细胞抗肿瘤效应的同时,也可能造成免疫耐受失衡或正常免疫亢进从而导致免疫性肝炎。本文主要通过对免疫检查点抑制剂的治疗机制,导致肝损伤的不良反应机制、危险因素以及发生率等方面进行回顾分析,并且对免疫检查点抑制剂导致肝损伤的治疗方法进行初步归纳。认为免疫检查点抑制剂在促进抗肿瘤免疫的同时,由于作用机制的非肿瘤组织靶点特异性,可能造成非同质化的免疫相关的肝损伤,治疗上以恢复免疫稳态为主。因此,免疫检查点抑制剂应用患者的管理往往需要在治疗窗、毒性和特定损伤治疗之间取得平衡,并开展多学科协作。     

免疫检查点抑制剂在结直肠癌中的应用以及未来发展方向

结直肠癌(colorectal cancer,CRC)是消化系最常见的恶性肿瘤之一,在我国,其发病率及死亡率处于逐年上升趋势,且总体预后相对较差.近年来,免疫治疗的基础和临床研究都获得了快速发展,已成为肿瘤研究的热点.其中,免疫检查点抑制剂已经被批准用于包括CRC在内的多种实体肿瘤的临床治疗.本文将重点阐述免疫检查点的作用、机制和免疫检查点抑制剂在CRC中应用的最新进展,以及影响其抗肿瘤疗效的因素.已经完成和正在进行的临床试验肯定了免疫检查点抑制剂在CRC的治疗中的潜力,尽管部分患者仍对免疫检查点治疗无应答.因此,探究免疫检查点抑制剂治疗CRC患者的敏感因素,对实现个体化精准治疗至关重要.未来,免疫检查点抑制剂有望和其他多种治疗方法相联合,提高患者反应率,延长患者的生存期.     

免疫检查点抑制剂相关性心肌炎发病机制研究进展

免疫检查点抑制剂已成为应用最广的肿瘤免疫疗法, 伊匹木单抗和纳武利尤单抗是其中的代表药物。但免疫检查点抑制剂的使用也带来许多免疫相关不良事件, 其中心肌炎是最致命的不良反应之一。免疫检查点抑制剂相关性心肌炎的发病机制尚不完全清楚, 主要包括自身免疫性T淋巴细胞浸润、调节性T细胞功能障碍、细胞因子、自身抗体的产生、遗传学因素、肠道微生物组等方面, 免疫检查点抑制剂相关性心肌炎的治疗及管理需要多学科专家的共同努力。     

免疫检查点抑制剂相关动脉粥样硬化性心血管疾病研究进展

近年来,免疫检查点抑制剂的出现改变了多种恶性肿瘤的治疗方式,但其常造成包括心血管系统在内的免疫相关不良事件。诸多对免疫检查点抑制剂治疗相关心血管不良事件的研究主要局限在心肌炎,而最近一些临床研究表明,免疫检查点抑制剂与动脉粥样硬化的发展和恶化可能相关。现就免疫检查点抑制剂相关动脉粥样硬化性心血管疾病可能的病理机制及临床意义进行综述,以期提高临床医生对动脉粥样硬化性心血管疾病的意识并警惕其发生。     

免疫检查点抑制剂相关性肠炎的诊疗进展

免疫检查点抑制剂具有恢复免疫系统识别和杀伤肿瘤细胞的能力, 近年来被应用于多种癌症的治疗。因其具有增强免疫系统活性, 破坏免疫稳态的作用, 可引起免疫相关不良反应。免疫相关不良反应可发生在各组织器官, 其中免疫检查点抑制剂相关性肠炎的发病率较高。本文结合国内外研究, 对免疫检查点抑制剂相关性肠炎的发病机制、临床表现、内镜特征及治疗进行综述, 并特别关注难治性肠炎的最新诊疗进展。     

免疫检查点抑制剂相关心脏毒性的研究进展

针对细胞毒T淋巴细胞相关抗原4(CTLA-4)、程序性死亡受体-1(PD-1)及其配体的单克隆抗体治疗已成为越来越多肿瘤的标准治疗。在取得良好疗效的同时,越来越多的患者出现治疗相关的毒性。免疫检查点抑制剂相关的心脏不良事件发生率虽然不足1%,但有可能相对更严重甚至是致命的,因此不断受到关注。本文将从发生机制、临床表现、诊断及治疗方面着重阐述免疫检查点抑制剂相关心脏毒性。     

咽喉癌化疗后免疫检查点抑制剂相关心肌炎1例

本文报告1例接受免疫检查点抑制剂治疗的咽喉癌患者，诊断为免疫检查点抑制剂相关心肌炎。结合相关文献分析该病的病因、临床表现、辅助检查、治疗方法及转归，探讨免疫检查点抑制剂相关心肌炎的诊疗思路。     

晚期原发性肝癌靶向及免疫治疗的研究进展

肝细胞癌（HCC）是原发性肝癌的主要组织学类型，占原发性肝癌的75%～85%。由于HCC起病隐匿，大多数患者初诊时即为晚期，手术切除、射频消融、肝动脉化疗栓塞等治疗效果有限，5年生存率较低。随着肿瘤分子信号通路和肿瘤微环境研究的不断深入，靶向治疗成为晚期HCC临床研究的热点，相继研发出了一系列靶向药物，如一线治疗的索拉非尼、仑伐替尼、多纳非尼以及二线治疗的瑞戈非尼、卡博替尼、雷莫芦单抗。除了靶向治疗外，近年来免疫检查点抑制剂在晚期HCC治疗中亦取得了突破性进展，相继研发出了一系列免疫检查点抑制剂，如纳武利尤单抗、帕博利珠单抗、卡瑞利珠单抗。这些新型靶向药物及免疫检查点抑制剂相继被批准用于晚期HCC治疗，为患者带来了更多的临床获益。     

食管癌免疫治疗研究进展

免疫治疗是近年来肿瘤治疗领域的热点,在各个瘤种中均进行了广泛的探索性研究。本文对食管癌免疫治疗的相关研究进展进行综述,全面分析免疫检查点抑制剂在食管癌中的治疗效果,同时寻找能够预测治疗效果的分子生物学标记。以食管癌、免疫治疗、免疫检查点抑制剂为关键词进行文献检索,共检索中文文献6篇,英文文献27篇,排除10篇,最终对23篇文献进行分析。在NCCN治疗指南中,错配修复蛋白缺失突变(dMMR)和微卫星高度不稳定(MSI-H)的患者应用PD-1单抗是晚期食管癌的标准二线治疗。无论是免疫单药、免疫联合治疗在食管癌一线、二线以及新辅助治疗中都进行了尝试。免疫治疗在食管癌治疗中显示出一定的生存获益,筛选能够预测免疫检查点抑制剂疗效的生物学标记物是提高疗效的关键。     

Does immune checkpoint inhibitor exhibit limited efficacy against non-viral hepatocellular carcinoma?: A review of clinical trials

Immunotherapy with immune checkpoint inhibitors has been shown to be beneficial for cancers originating from various organs. In May 2020, combination therapy with anti-programmed death-ligand 1 antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was approved as a novel first-line systemic therapy for hepatocellular carcinoma (HCC). The number of patients with HCC not caused by hepatitis virus infection (non-viral HCC), including non-alcoholic steatohepatitis (NASH)-related HCC, has been increasing in recent years. Recently, Pfister and colleagues reported that immune checkpoint inhibitors may exhibit limited efficacy against NASH-related HCC, based on basic research and clinical data. This review will discuss the mechanism of impaired tumor immune surveillance in NASH and analyze the results of previously published clinical trials of immune checkpoint inhibitors to investigate whether patients with non-viral HCC are less likely to benefit from immunotherapy with immune checkpoint inhibitors. Furthermore, we also discuss the possibility of enhancing the therapeutic effect of immune checkpoint inhibitors for NASH-related HCC by combining anti-VEGF agents.     

Efficacy of immune checkpoint inhibitors in the treatment of non-small cell lung cancer patients with different genes mutation: A meta-analysis

Background:Latest clinical trials have proved the better overall survival (OS) for the use of immune checkpoint inhibitors verse chemotherapy in non-small cell lung cancer (NSCLC) patients. However, we still have no clear ideas of the factors which could affect the efficacy of immune checkpoint inhibitors. Cancer, essentially, is a disease related to genes mutation. Therefore, we conducted a systematic review and meta-analysis to compare efficacy of immune checkpoint inhibitors for NSCLC patients with different genes mutation.Methods:PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched for all clinical trials in NSCLC until December 16, 2019. The hazard ratio (HR) and 95% confidence intervals (CIs) of OS or progression-free survival (PFS) were used.Results:A total of 4453 patients from 7 randomized controlled trials (RCTs) were included. Immune checkpoint inhibitors significantly prolonged the OS (HR, 0.67; 95% CI, 0.60–0.67) in NSCLC patients having epidermal growth factor receptor (EGFR) wild-type versus chemotherapy. Meanwhile, they prolonged the OS (HR, 0.61; 95% CI, 0.39–0.94) in NSCLC patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. No matter PD-L1 tumor proportion scores were >1% or <1%, immune checkpoint inhibitors were more effective than chemotherapy (HR, 0.64; 95% CI, 0.55–0.75).Conclusion:Immune checkpoint inhibitors are more efficacious than chemotherapy in NSCLC patients with EGFR wild-type, KRAS mutation, and any PD-L1 tumor proportion scores.     

免疫检查点抑制剂相关心脏毒性的研究进展

免疫检查点抑制剂(ICI)通过阻断肿瘤细胞的免疫逃逸,调动自身免疫反应达到治疗肿瘤的目的.ICI可导致多种免疫相关不良反应,其中心脏毒性是少见但致命的不良反应.随着ICI在临床中使用的增加,其导致的心脏毒性逐渐引起更多关注.本文就ICI相关心脏毒性临床表现、机制、诊治及预后进行综述.     

Immunotherapy for thymoma

Thymic epithelial tumors (TETs) are rare thymic neoplasms. There are approximately 1.5 cases per million TETs per year. They are the most common anterior mediastinal tumors in adults. Due to limited activity of available treatment options novel strategies and treatment options are needed and treatment with immune checkpoint inhibitors is an attractive option. Thymic epithelial tumors have one of the lowest tumor mutational burden among all cancer in adults, but high expression of PD-L1 on tumor cells and abundant CD8+ lymphocytes provide a strong rational for implementing immune checkpoint inhibitors (ICIs) which target PD-1/PD-L1 pathway in the treatment of TETs. Few small early stage clinical trials were published so far evaluating efficacy of pembrolizumab and avelumab in thymoma and thymic carcinoma patients. Al trials showed reasonable response rates and progression-free survival. Higher PD-L1 expression was predictor of response in all trials. However, increased incidence of immune-related adverse events was seen in TET patients treated with immune checkpoint inhibitors compared to patients with other cancers. At the moment, ICIs are not standard of care for patients with TET and larger trials are needed to establish the right role of ICIs regarding efficacy and safety of these agents.     

Immune checkpoint blockade for the treatment of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high recurrence rate. Currently, tyrosine kinase inhibitors (TKIs) are the first‐line treatment for cases refractory to conventional therapies. However, the acquisition of somatic mutations can result in TKI resistance. Clinical evidence suggests that acquired immunity contributes to the suppression of tumor recurrence, indicating the potential of induced antitumor immune reaction for the treatment of HCC. Recently, immune checkpoint inhibitors have become available for the treatment of malignancies. They are effective regardless of the response to prior therapies and a durable effect can be expected, which should be attributed to an adaptive immunity to HCC components. The results of phase I/II trials of nivolumab, an anti‐programmed cell death‐1 antibody, showed that 20% of patients showed objective response and that nivolumab was effective regardless of prior sorafenib treatment and viral status. Nivolumab received expedited Food and Drug Administration approval in 2017 for the treatment of advanced HCC after failure or intolerance to sorafenib. However, the majority of the patients remain refractory, likely due to the solid immune suppressive status, which involves many stromal cells, humoral mediators, and suppressive checkpoint molecules. Therefore, current clinical trials are focusing on how immunosuppressive conditions in HCC might be overcome using immune checkpoint inhibitors in combination with different types of immune checkpoint blockades, TKIs, and other conventional treatments. The development of immune checkpoint inhibitors is rapidly progressing and these inhibitors are likely to be key agents for HCC treatment in the near feature.     

免疫检查点抑制剂的心脏毒性

随着免疫检查点抑制剂（ICIs）的广泛使用,由其带来的不良反应是临床医生面临的巨大挑战,心脏毒性（尤其是心肌炎）是其严重的不良反应。由于发病率低,目前对于免疫检查点抑制剂引起的心脏毒性知之甚少,具体机制、预测因子、危险因素、管理方案及治疗方案并不明确,本综述整理ICIs心脏毒性可能的机制、危险因素、心脏毒性类型及管理和治疗方案,以期待更多医生关注,为肿瘤患者更好的进行治疗指导。     

Immunotherapy in aggressive B-cell lymphomas

The idea that the immune system could be co-opted to treat cancer is not new; it has existed for centuries. However, what is new is the advancement of our understanding of how the immune system is regulated and how a tumor evolves to evade an immune response. This knowledge, combined with modern technologies to manipulate the immune system, both pharmacologically and genetically, has led to the realization of immuno-oncology as a new frontier in cancer therapeutics. This review will focus on pharmacologic immunotherapies in aggressive B cell lymphomas: checkpoint inhibition and bispecific antibodies. The success of checkpoint inhibitors in this heterogenous collection of diseases has largely been limited to those that genetic aberrations involving genes for checkpoint ligands, whereas bispecific antibodies appear to be more broadly efficacious but responses are short-lived. Investigation into the tumor microenvironment for each of the aggressive B cell lymphoma histologies, and interrogation of mechanisms of resistance as well as predictors of response to these immunotherapy approaches, will undoubtedly identify rational combinations as well as new therapeutic targets such that outcomes can be improved across these diseases.     

肺癌的免疫治疗进展

目前肺癌的治疗手段是以手术、放疗、化疗和靶向治疗为主的综合治疗,虽然患者的生存期已明显延长,但至今仍是全世界癌症相关死因的主要原因.不断揭示肺癌新的发病机制、探讨新的治疗策略,仍是该领域专家需要共同面对的世界性难题.早期的研究已经初步证明多种肿瘤疫苗、免疫检查点抑制剂、过继性免疫等对肺癌的有效性,目前部分研究已进入Ⅲ期临床.PD-1、PD-L1等免疫检查点抑制剂已批准进入临床并取得理想的效果.随着临床研究的不断开展,越来越多的数据表明,在肺癌的个体化、整体化的治疗策略中适时介入免疫治疗将使更多的肺癌患者获益.     

Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer

Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with differentclinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.