免疫检查点抑制剂治疗宫颈癌的研究进展

宫颈癌是常见的妇科恶性肿瘤,目前以单药顺铂为基础的同步放化疗是局部晚期宫颈癌的标准治疗方案。与单纯放化疗相比,在同步放化疗中采用免疫抑制剂联合方案有可能提高局控率和减少远处转移。近年来,免疫检查点抑制剂(ICIs)作为宫颈癌的潜在治疗靶点被广泛研究。ICIs可以改善免疫细胞的活化从而增强机体的抗肿瘤免疫力。综述了ICIs的作用机制,并回顾了各类单抗药物的临床效果、优缺点以及ICIs的联合治疗,并从耐药性以及药物不良事件方面为宫颈癌患者的免疫治疗选择提供参考依据。     

免疫检查点抑制剂致免疫相关肝损伤的研究进展

近年来, 免疫检查点抑制剂(ICIs)在肿瘤患者的治疗中取得了很大进展, 延长了患者的生存期。然而, 在其增强免疫抗肿瘤的同时也可能造成免疫耐受失衡从而导致不同程度的免疫相关不良事件(irAEs)发生, ICIs致免疫相关肝损伤(ILICI)是其中较为常见的一种。主要对ILICI的定义、流行病学及危险因素、发病机制、病理及临床表现、治疗、复发及再治疗的研究进展进行综述。     

免疫检查点抑制剂相关外周血生物标志物的研究进展

肿瘤精准治疗已经进入以免疫检查点抑制剂（ICIs）为代表的免疫治疗时代。以肿瘤组织为基础的检测,如程序性死亡受体配体-1和肿瘤突变负荷等是临床用于筛选ICIs获益人群的常见生物标志物。但基于组织的检测存在组织标本不足和需要进行有创、复杂的操作等缺陷,限制了其广泛应用,而近来兴起的外周血生物标志物为这些缺陷提供了一种非侵入性的解决方案。本综述总结了ICIs相关外周血生物标志物的研究进展,以期为临床筛选ICIs获益人群提供参考。     

免疫检查点抑制剂在肺癌治疗中不良事件的分析

在治疗肺癌的过程中,免疫治疗逐渐成为最热门的治疗手段,一线免疫治疗联合化疗开启了肺癌治疗的新格局。多种免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的获批,掀起了免疫治疗的热潮。但是,在治疗过程中,由于激活免疫细胞或者达到免疫最大化,部分患者会出现不同程度的免疫相关不良事件(im...     

肠道菌群影响免疫检查点抑制剂治疗癌症的研究进展

人体肠道内寄生着约1 014 个共生菌群,这些菌群可以帮助分解人体内的食物,其代谢产物能影响人体消化能力、抗自身免疫性疾病的能力等,是人体内不可忽视的重要“器官冶。最近的研究发现,人体内的肠道菌群可以影响免疫检查点抑制剂(Immune-checkpoint blockers,ICB)治疗癌症。本文将结合近几年的研究成果,对癌症免疫治疗后出现的不良反应、肠道菌群及肠道菌群如何影响免疫检查点抑制剂(ICB)治疗癌症的研究进展进行总结,最后对肠道菌群影响癌症治疗进行展望,以期能够为研究肠道菌群与癌症治疗的关系提供理论依据。     

免疫检查点抑制剂在脑胶质瘤中的研究进展及治疗策略

目前针对免疫检查点的治疗在多种颅外肿瘤中已取得显著进展和确切疗效.但在脑胶质瘤中,由于其特殊的解剖及免疫环境,免疫检查点抑制剂的疗效仍不确切.随着近期相关基础研究和临床试验的相继进展,针对免疫检查点的治疗在脑胶质瘤中也表现出巨大潜力.因此,免疫检查点抑制剂有望成为脑胶质瘤治疗的新方向.本文对免疫检查点抑制剂在脑胶质瘤中...     

PD-1抑制剂免疫相关不良反应的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICI)的应用是肿瘤治疗领域的重大突破,是恶性肿瘤患者新的选择和希望.国家食品与药品管理监督局(Chinese Food and Drug Administration,CFDA)批准程序性细胞死亡蛋白-1(programmed cell de...     

免疫治疗中发生免疫相关不良事件的23例晚期实体瘤患者的临床疗效分析

目的 观察经免疫检查点抑制剂治疗并出现免疫相关不良事件(immune-related adverse events,irAEs)的肿瘤患者的基线特征及临床疗效.方法 回顾性分析出现免疫相关不良事件的肿瘤患者的临床效果,评价其客观有效率、无进展生存时间及总生存时间.结果 23例患者发生irAEs的中位时间为3.17个月,...     

非小细胞肺癌免疫检查点抑制剂相关性肺炎研究进展及中西医结合治疗

免疫检查点抑制剂（ICIs）主要包括细胞毒性T淋巴细胞抗原4(CTLA-4)抑制剂和程序性细胞死亡蛋白1/配体1(PD-1/PD-L1)抑制剂,为非小细胞肺癌（NSCLC）患者带来显著的治疗效益。但是,在增强机体抗肿瘤免疫反应的同时,ICIs产生免疫相关不良事件（irAEs）,包括免疫检查点抑制剂相关性肺炎（CIP）。虽然CIP临床发病率较低,但在一些严重病例中可能导致免疫治疗的延迟或终止,甚至危害生命。本文拟从CIP的临床表现、病理特征、生物学机制、易感人群、诊断与鉴别诊断以及中西医结合治疗等角度进行总结,以期更加清晰地认识CIP。     

免疫检查点抑制剂治疗骨髓增生异常综合征的研究进展

免疫检查点抑制剂(ICI)通过抑制肿瘤细胞逃逸、增强免疫应答而作为MDS潜在的治疗方式,本文回顾性分析了针对PD-1/PD-L1和CTLA-4的ICI治疗MDS的临床试验,分析了ICI治疗的疗效和不良反应.ICI单药或与去甲基化药物(HMA)合用是可耐受的.尽管目前单药ICI治疗的疗效有限,但和HMA可能具有协同作用,...     

An autopsy case study of lymphocytic hypophysitis induced by nivolumab treatment for esophageal malignant melanoma

Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies are effective against malignant tumors. However, they induce unique adverse events known as immune-related adverse events. Hypophysitis is one of the most frequent immune-related adverse events of anti-cytotoxic T-lymphocyte antigen-4 therapies. However, there have been few reports describing the pathological findings of hypophysitis induced by anti-programmed death-1 antibodies. The present case is the first autopsy case of hypophysitis induced by nivolumab monotherapy, an anti-programmed death-1 antibody. Pathologically, lymphocytes infiltrated the anterior lobe of the pituitary gland, and the number of pituitary cells, especially adrenocorticotropic hormone-positive cells, decreased. However, necrosis and remarkable fibrosis were not observed. Immunohistologically, some pituitary cells expressed programmed death-ligand 1. Lymphocytes were predominantly CD8-positive T cells, and CD68-positive macrophages and CD20-positive B-cells were also observed. IgG and C4d were deposited on pituitary cells, but IgG4 (a subclass of nivolumab) was not detected. These findings indicate that type IVc and type II hypersensitivity mechanisms may occur in hypophysitis induced by anti-programmed death-1 antibodies and that the inflammatory mechanisms underlying hypophysitis induced by anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4 antibodies are different.     

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.     

VISTA: Coming of age as a multi-lineage immune checkpoint

The immune response is governed by a highly complex set of interactions among cells and mediators. T cells may be rendered dysfunctional by the presence of high levels of antigen in the absence of co-stimulation while myeloid cells may be programmed towards an immunosuppressive state that promotes cancer growth and metastasis while deterring tumor immunity. In addition, inhibitory programs driven by immune checkpoint regulators dampen anti-tumor immunity. The ideal cancer immunotherapy treatment will improve both cross-priming in the tumor microenvironment and relieve suppression by the inhibitory checkpoints. Recently, blockade of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has elicited impressive results, but not in all patients, so additional targets are under investigation. V-set immunoglobulin domain suppressor of T cell activation (VISTA) is a novel immunoregulatory receptor that is broadly expressed on cells of the myeloid and lymphoid lineages, and is frequently implicated as a poor prognostic indicator in multiple cancers. Importantly, antibody targeting of VISTA uniquely engages both innate and adaptive immunity. This, combined with the expression of VISTA and its non-redundant activities compared to other immune checkpoint regulators, qualifies VISTA to be a promising target for improving cancer immunotherapy.     

IgG4‐related hypophysitis is highly prevalent among cases of histologically confirmed hypophysitis

IgG4‐related disease is an immune‐mediated disease with manifestations in most organ systems among them the pituitary gland. To date, few cases of histologically confirmed cases of IgG‐related hypophysitis have been reported. The aim of this study was to retrospectively determine the prevalence of IgG4‐related hypophysitis among cases previously diagnosed as primary hypophysitis (lymphocytic hypophysitis, granulomatous hypophysitis and hypophysitis not otherwise specified). Histological and immunohistochemical analysis revealed that 12 of 29 cases (41.4%) previously diagnosed as primary hypophysitis fulfilled the criteria for IgG4‐related disease and, thus, IgG4‐related hypophysitis should always be considered in the differential diagnosis of primary hypophysitis. All cases of IgG4‐related hypophysitis showed a dense lymphoplasmacytic infiltrate with more than 10 IgG4‐positive cells per high power field and a ratio of IgG4/IgG‐positive cells of more than 40%, whereas storiform fibrosis was an inconsistent histological feature and was also seen in few cases of non‐IgG‐related hypophysitis, thus lacking sensitivity and specificity. Obliterative phlebitis was not seen in any case. Thus, histological criteria defined for IgG4‐related disease in other organs should be modified for IgG4‐related hypophysitis, accordingly.     

Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.     

Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) have proved to be groundbreaking in the field of oncology. However, immune system overactivation from ICIs has introduced a novel medical entity known as immune-related adverse events (irAEs), that can affect any organ or tissue. ICI-induced inflammatory arthritis (ICI-IIA) is the most common musculoskeletal irAE and can lead to significant morbidity and limitation in anti-cancer therapy.     

Tumor infiltrated immune cell types support distinct immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer

The evaluation of PD-L1 expression alone has limitations in predicting clinical outcome in immune-checkpoint inhibitors (ICI). This study aimed to evaluate the predictive and prognostic effects of the presence of various immune cells in pretreatment tissue samples and to identify determinants associated with response in patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1 blockade. Immune cell distribution was heterogeneous and the most dominant immune cell type was T cells. Patients with durable clinical benefit (DCB) showed significantly higher PD-L1 expression. The ratio of tumor/stroma region of T cell, B cell, and macrophage was significantly higher in patient with DCB. High intratumoral T- and B-cell density (≥median) was associated with DCB in the low PD-L1 expression (<50%) group. In univariate analyses, the overall survival (OS) benefit was shown according to intratumoral B-cell density (p = 0.0337). The incidence of hyperprogressive disease (HPD) was 13.0%. The Chi-square test revealed that HPD was significantly associated with intratumoral B-cell density but not T-cell or macrophage density. Our results demonstrate different predictive and prognostic values for infiltrating immune cells in tumor tissue, which may help in selecting patients for ICI.