免疫检查点抑制剂联合化学疗法在老年晚期非小细胞肺癌治疗中的应用进展

肺癌是全世界癌症相关死亡的主要原因,其中非小细胞肺癌是最常见的亚型。以免疫检查点抑制剂为代表的免疫治疗通过机体免疫系统发挥有效的抗肿瘤作用。抗PD-1抗体Pembrolizumab联合化疗治疗的≥65岁晚期无驱动基因转移性非鳞状非小细胞肺癌患者总生存期获益,但晚期转移性鳞状非小细胞肺癌患者并未从治疗中获益;Pembrolizumab联合化疗治疗的老年晚期非小细胞肺癌患者药物相关不良事件增加。与单纯化疗对比,抗PD-1抗体Nivolumab联合化疗治疗的晚期非小细胞肺癌患者并未获益。抗PD-L1抗体Atezolizumab联合化疗治疗的老年晚期非小细胞肺癌患者获益,但药物相关不良事件的发生率较单纯化疗明显增加。抗PD-1抗体Nivolumab和CTLA-4抑制剂Ipilimumab双免疫治疗的PD-L1表达阳性晚期非小细胞肺癌患者总生存期显著获益,但>75岁的患者并未获益,且药物相关不良事件明显增加。抗PD-L1抗体Durvalumab与CTLA-4抑制剂Tremelimumab双免疫联合化疗治疗的老年晚期非鳞状非小细胞肺癌患者总生存期及无进展生存期均获益,但药物相关不良反应发生率...     

冷肿瘤的免疫治疗

免疫治疗是继手术、放疗、传统化疗后的第四大肿瘤治疗手段.基于患者自身的免疫系统治疗癌症的理念已经开发了许多的治疗方法.研究证明最有效的免疫治疗是免疫检查点抑制剂(CPIs),它们通过阻断免疫抑制机制发挥作用.CPIs临床应用最好的例证是基于PD-1/L1和CTLA-4的发现,后者获得了诺贝尔奖.由于肿瘤微环境的异质性,...     

免疫检查点抑制剂在晚期非小细胞肺癌治疗中的应用进展

随着程序性死亡受体1(PD-1)、程序性死亡配体1(PD-L1)以及细胞毒性T淋巴细胞抗原4(CTLA-4)等免疫检查点的发现，免疫检查点抑制剂（ICI）逐渐成为肿瘤治疗领域中最有前景的方法之一，已被证实可以提高晚期非小细胞肺癌（NSCLC）患者的生存率。与化疗相比，对于肿瘤细胞表面PD-L1高表达的晚期NSCLC患者，抗PD-1/PD-L1治疗后生存期显著延长且不良反应较少。抗CTLA-4药物单药治疗效果有限，通常与PD-1/PD-L1药物联合可进一步提高抗肿瘤效果。另外一些新型免疫检查点抑制剂，如依吉利单抗、替拉戈鲁单抗等在临床试验中也表现出一定的抗肿瘤作用，未来在晚期NSCLC患者的治疗中或许能提供帮助。对ICI在NSCLC治疗中的临床应用进行总结，同时对未来免疫治疗的发展和预测性生物标志物进行展望，可以为晚期NSCLC患者的治疗提供新的靶点和思路。     

免疫检查点抑制剂相关性肝损伤

<正>免疫调节疗法极大地改善了晚期肿瘤转移患者的生存率,已经成为最具前景的新型癌症治疗方法。肿瘤免疫治疗由于其疗效卓越和方法创新,在2013年被Science杂志评为年度十大科学突破之首。免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)是目前肿瘤免疫治疗较成功的领域和研究的热点,并摘得2018年诺贝尔生理学或医学奖。细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性细胞死亡蛋白-1及其配体(PD-1     

PD-1抑制剂介导内分泌不良反应报道并文献复习

免疫检查点抑制剂( immune checkpoint inhibitors, ICPIs)的出现是近年来肿瘤治疗领域的重大突破,这类分子通过阻断细胞毒性T 淋巴细胞抗原4 ( CTLA-4)、程序性细胞死亡蛋白1( PD-1)或其配体( PD-L1)来调节抑制性免疫应答.但免疫治疗相关不良反应( immune-rel...     

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.     

EB病毒相关胃癌免疫治疗的研究进展

EB病毒相关胃癌（EBVaGC）是一种具有独特病理特征的胃癌亚型，具有高表达免疫检查点蛋白和高淋巴细胞浸润特性。因此，免疫疗法有望成为EBVaGC新的治疗策略。免疫检查点阻断疗法是目前研究最多的一种免疫治疗手段，如程序性细胞死亡受体1(PD-1)/程序性细胞死亡配体1(PD-L1)抑制剂、细胞毒性T淋巴细胞相关抗原4(CTLA-4)抑制剂。目前，治疗EBVaGC的PD-1/PD-L1抑制剂有Avelumab、Pembrolizumab、Nivolumab、Toripalimab、Camrelizumab等，CTLA-4抑制剂有Ipilimumab、Tremelimumab。除此之外，还有利用STING、BARF1、MHC、CXCL8、NK细胞等分子或细胞的免疫治疗手段。但免疫疗法治疗EBVaGC的临床研究尚少，其具体疗效还有待于进一步验证。     

PD-1/PD-L1在肝细胞癌免疫治疗中的应用现状及进展

肝细胞癌(hepatocellular carcinoma, HCC)是我国最常见的恶性肿瘤之一,发病率高,预后差,疾病进展迅速且隐匿性强,多数患者初诊时已为中晚期,严重威胁我国人民的生命健康。在免疫疗法兴起之前,放化疗、分子靶向药物为主要治疗方法。研究报道免疫检查点PD-1/PD-L1抑制剂或与其他方案联用,不仅能够促进机体正常免疫功能的恢复,还具有显著的抗肿瘤作用。本文总结了PD-1/PD-L1单药及联合抗血管生成剂、CTLA-4、分子靶向药物等其他新型方案在HCC治疗中可能的作用机制及研究现状,为HCC患者的临床免疫治疗提供参考。     

PD-1/PD-L1在肝细胞癌预后判断作用中的研究进展

肝细胞癌(HCC)是肝脏最常见的原发性肿瘤,目前治疗手段包括手术切除、射频消融、经动脉化疗栓塞术、免疫治疗等。程序性死亡蛋白-1(PD-1)是一种抑制性免疫检查点分子,PD-1及其配体(PD-L1)在HCC肿瘤免疫过程中诱导形成免疫抑制微环境,促进肿瘤增殖和转移。研究发现在肝癌患者接受手术切除、免疫治疗或其他常规治疗后,PD-1/PD-L1高表达均与患者生存率有关,但PD-1/PD-L1作为临床预后标志物有其局限性。     

PD-1抗体/PD-L1抗体在结直肠癌治疗中的应用现状及展望

结直肠癌是第二大最常见的肿瘤死亡原因。免疫治疗逐渐成为结直肠癌手术切除等常规治疗方式以外的另一种治疗方法。目前对抗PD-1/抗PD-L1药物疗效及不良反应的报道各不相同。本文将从PD-1信号通路及其阻断剂、PD-1/PD-L1抗体在结直肠癌中的临床应用、结直肠癌患者对免疫治疗的抵抗、PD-1/PD-L1抗体治疗的不良反应、预测PD-1/PD-L1抗体治疗疗效的生物学标志物等方面进行综述。     

Pulmonary metastasectomy in the era of targeted therapy and immunotherapy

Metastatic melanoma is a fatal malignancy with a high mortality and morbidity. Since the early 1970s, available medical therapies were limited in improving survival. Surgery represented the best chance for a cure. However, surgery could only be offered to selected patients. The current landscape of treatment has radically evolved since the introduction of targeted and immunotherapies including BRAF and MEK inhibitors, and checkpoint blockers, like PD-1 and CTLA-4 antibodies. These new therapies have seen survival rates matching, and in some cases surpassing, that of surgery. Anti-PD1 and CTLA-4 combination treatments are associated with severe side effects and BRAF and MEK inhibitor combinations may trigger initial tumour responses but prolonged use have resulted in the development of resistant tumour clones and disease relapse. This review examines the role of pulmonary metastasectomy for lung metastasis from malignant melanoma in the current landscape of effective targeted therapy and immunotherapy.     

Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes;therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyteassociated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.     

The intimate relationship between gut microbiota and cancer immunotherapy

Immunotherapy is widely used to treat a large variety of malignancies and has revolutionized the therapeutic approach to cancer. Major efforts are ongoing to identify biomarkers that predict response to immunotherapy as well as new strategies to improve ICI efficacy and clinical outcomes. Studies have shown that the gut microbiome determines the extent to which ICIs may invigorate the anticancer immune response. Here, the authors review recent studies that have described the effects of the gut microbiota on the efficacy of CTLA-4 and PD-1 inhibitors and outline potential future clinical directions of these findings.     

Clinical treatment of cholangiocarcinoma: an updated comprehensive review

Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA).The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types.When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor.In order to ameliorate patients’ survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.     

Immunotherapy for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is presented frequently in late stages that are not amenable for curative treatment. Even for patients who can undergo resection for curative treatment of HCC, up to 50% recur. For patients who were not exposed to systemic therapy prior to recurrence, recurrence frequently cannot be subjected to curative therapy or local treatments. Such patients have several options of immunotherapy(IO). This includes programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte...     

Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2

Programmed death-1 (PD-1) is a member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. The high-resolution crystal structure of the complex formed by the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 inhibitory complexes. Furthermore, our structure also provides insights into the association between PD-1 and PD-L1 and highlights differences in the interfaces formed by the two PD-1 ligands (PD-Ls) Mutagenesis studies confirmed the details of the proposed PD-1/PD-L binding interfaces and allowed for the design of a mutant PD-1 receptor with enhanced affinity. These studies define spatial and organizational constraints that control the localization and signaling of PD-1/PD-L complexes within the immunological synapse and provide a basis for manipulating the PD-1 pathways for immunotherapy.     

程序性死亡受体1/程序性死亡配体1免疫检测点阻滞剂在实体瘤治疗中的临床研究

近年来程序性死亡受体1/程序性死亡配体1(PD-1/PD-L1)免疫检测点阻滞剂在实体瘤治疗上取得振奋人心的效果。PD-1主要表达于活化的T、B细胞,在限制自身免疫及过度炎症反应方面起重要作用;肿瘤微环境中PD-1/PD-L1的高表达使T细胞活性受到过度抑制,从而发生肿瘤免疫逃逸;PD-L1表达水平可能是预测检测点阻滞剂疗效的标志物。免疫治疗因其持久的反应性及较小毒副作用使部分肿瘤患者获益明显。本文旨在阐述主要的PD-1/PD-L1检测点阻滞剂(单抗)近年来在恶性黑色素瘤、肺癌、尿路上皮癌、肾细胞癌等治疗上研究的现状并在获益人群中筛选出可能具有价值的生物学标志物。     

Colorectal cancer and immunity:what we know and perspectives

Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer.In particular,the density of T CD8+and CD45+lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor.Other immune subsets,as macrophages,natural killer cells or unconventionnal lymphocytes,seem to play an important role.Induction of regulatory T cells(Tregs)or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response.The development of these mechanisms is a major obstacle to the establishment of an effective immune response,but also to the use of immunotherapy.Although im-munotherapy is not yet routinely used in colorectal cancer,we now know that most treatments used(chemotherapy and biotherapy)have immunomodulatory effects,such as induction of immunogenic cell death by chemotherapy,inhibition of immunosuppression by antiangiogenic agents,and antibody-dependent cytotoxicity induced by cetuximab.Finally,many immunotherapy strategies are being developed and tested in phaseⅠtoⅢclinical trials.The most promising strategies are boosting the immune system with cytokines,inhibition of immunoregulatory checkpoints,vaccination with vectorized antigens,and adoptive cell therapy.Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.     

胰腺癌免疫治疗及其最新进展

胰腺癌是一种预后极差的恶性肿瘤,胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)是其中最常见的类型,患者被诊断时多为晚期。晚期患者在所有患者中所占比例可超过80%,这类人群的治疗主要是全身化疗,但化疗效果有限。大多数针对PDAC新疗法的研究与开发则开始关注新辅助治疗以及对各种间质成分的靶向,并且旨在缓解免疫抑制的药物疗法也备受关注,但不管是PD-1/PD-L1抗体还是CTLA-4抗体,抑或是两类药物的联合,在改善胰腺癌患者的生存方面均未能获得显著的成效。由此,我们猜测,通过对其他潜在免疫疗法的探索与研究,或许可以给胰腺癌的治疗带来新的希望。本综述旨在总结胰腺癌免疫治疗及其最新进展,通过对其进一步的理解来认识此疾病带来的治疗难点,从而有望改善其治疗策略。     

Phenotypic Characteristics of PD-1 and CTLA-4 Expression in Symptomatic Acute Hepatitis A

Background/Aims

The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA).

Methods

Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry.

Results

PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1: 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4: 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH.

Conclusions

Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.