靶向免疫检查点PD-1/PD-L1的肿瘤分子影像学研究进展

程序化细胞死亡受体-1（PD-1）及其配体（PD-L1）抑制剂通过阻断PD-1与PD-L1的结合使负向调控信号受阻,重新激活T淋巴细胞,增强免疫应答。临床试验结果显示PD-1/PD-L1抑制剂对多种肿瘤有明确的疗效,且疗效与肿瘤PD-1/PD-L1的表达水平相关。因此在免疫治疗之前检测患者PD-1/PD-L1的表达水平对筛选可能获益的患者、预测免疫治疗反应尤为重要。靶向PD-1/PD-L1的分子影像学方法能够在活体内无创、全面、准确地显示肿瘤PD-1及PD-L1的表达水平,成为国内外的研究热点。笔者对靶向PD-1/PD-L1肿瘤分子影像学的研究进展作一综述。     

靶向PD-L1的PET/CT分子探针研究进展

程序性死亡受体1（PD-1）/ 程序性死亡配体1（PD-L1）是肿瘤免疫治疗中重要的免疫检查点,PD-L1主要在肿瘤细胞和肿瘤相关髓样细胞中表达。放射性核素标记的靶向PD-L1分子探针可被PET/CT检测,使PD-L1表达在分子层面可视化,是指导免疫治疗的重要手段。靶向PD-L1的PET探针有抗体、多肽、小分子及其他类,目前部分探针应用于临床。笔者对靶向PD-L1的分子探针及临床应用进行综述。     

放疗与免疫检查点抑制剂联合治疗肿瘤的研究进展

放疗主要是通过诱导DNA损伤直接杀死肿瘤细胞,还可通过激活宿主免疫成分间接作用于肿瘤组织,从而诱导抗肿瘤免疫反应,但在某些情况下也能导致免疫抑制。近年来,免疫检查点抑制剂的发展在多种肿瘤中显示出巨大的治疗潜力,其中又以程序性死亡受体1（PD-1）和程序性死亡配体1（PD-L1）抑制剂最具代表性,但其在一些免疫“冷”肿瘤中并不起作用。基于放疗与免疫检查点抑制剂在肿瘤组织中的作用机制,研究人员发现PD-1/PD-L1抑制剂可以解除放疗导致的免疫抑制,而放疗可以使免疫“冷”肿瘤转换为免疫“热”肿瘤从而受益于免疫治疗,因此,二者的联合应用引起了研究人员的广泛关注。笔者将主要介绍放疗与PD-1/PD-L1抑制剂联合应用的作用机制,总结其最新的研究进展,这对临床选择合适的获益人群、评估疗效与预后具有重要意义。     

肿瘤免疫治疗相关PD-(L)1 PET靶向核素探针应用研究进展

免疫治疗已经进入多种肿瘤的临床治疗。程序性细胞死亡分子-1/配体-1(PD-1/PD-L1)免疫检查点的阻断治疗是目前最重要的肿瘤免疫治疗方法。目前临床上通过免疫组织化学方法(IHC)检测肿瘤患者PD-L1表达情况并筛选适应证,但PD-L1表达异质性、动态变化性以及样本取材受限等因素限制了经此法对肿瘤患者体内PD-L1表达情况的评估价值。 PD-(L)1 PET成像利用放射性标记分子在空间和时间上非侵入性地评估 PD-(L)1 的表达,和免疫组织化学互补使用,理论上存在不可比拟的优势。本文就 PD-(L)1 探针分子成像原理、临床研究及存在问题等最新进展做一综述。     

靶向PD-1/PD-L1放射性核素分子探针及其在恶性肿瘤中的应用

程序性细胞死亡受体1（PD-1）及其配体（PD-L1）免疫治疗已成为一种治疗多种恶性肿瘤的重要方法,但仅有部分患者临床获益,其影响因素之一是恶性肿瘤PD-1/PD-L1的表达水平。使用放射性核素标记完整单克隆抗体和抗体片段等制成靶向PD-1/PD-L1放射性核素分子探针进行显像,可无创、实时、动态地监测肿瘤PD-1/PD-L1的表达并量化其表达水平,进而筛选适宜治疗的患者、全面评估治疗疗效和预后。笔者综述了靶向PD-1/PD-L1放射性核素分子探针及其在恶性肿瘤中的应用。     

肿瘤免疫治疗疗效评价标准—iRECIST解读

近年来,肿瘤免疫治疗迅猛发展,而现有世界卫生组织标准或实体瘤疗效评价标准(response evaluation criteria in solid tumor,RECIST)无法对免疫治疗疗效进行准确的解读和确切的评估,尤其是反映肿瘤缓解或进展的关键问题—肿瘤负荷的变化。基于此,RECIST工作组结合临床肿瘤免疫治疗实践改良的实体肿瘤疗效评价标准（RECIST版本1.1）制定了一个新的肿瘤免疫治疗疗效评价标准—实体瘤免疫治疗疗效评价标准（immune response evaluation criteria in solid tumor,iRECIST）,并在2017年第18期的The Lancet Oncology上发表。该标准详细定义了实体瘤测量及肿瘤大小评价的标准方法,以期在后续肿瘤免疫治疗临床试验中得以验证。作者对这一新的标准作一介绍。     

肿瘤免疫治疗的分子影像监测

使用检查点抑制剂的生物免疫疗法已发展成为一种有前途的癌症治疗方法,但免疫抑制剂治疗并非对所有患者都有效,而且还普遍存在严重的免疫相关不良反应。分子影像可以从分子和细胞水平识别肿瘤微环境中免疫检查点（IC）的表达,不仅有助于筛选出适合免疫疗法的患者,还可以监测肿瘤的治疗反应。笔者综述了分子影像在靶向肿瘤IC治疗监测方面的...     

非小细胞肺癌治疗新时代:免疫治疗

免疫检查点抑制剂目前已成为晚期非小细胞肺癌患者除外手术、化疗、放疗、靶向治疗之外的又一重要选择.无论是一线还是二线治疗、鳞癌还是非鳞癌,免疫治疗均有可能带来优于传统化疗的治疗效果,尤其是对于PD-L1阳性患者.本文对免疫检查点抑制剂的临床疗效、分子标志物选择、联合治疗、耐药机制应用等进行述评.     

Current State of Combination of Locoregional Therapies with Immune Checkpoint Inhibition

Advances in immunotherapy have changed the landscape of oncology over the past decade. Still, most patients with solid organ tumors do not derive a durable benefit from immunotherapies. How these tumors evade treatment has not been fully elucidated, but several studies are seeking ways to stimulate treatment response in these immunologically quiescent tumors. Of these, the combination of locoregional therapy with immune checkpoint inhibition is of interest to the interventional radiologist. This brief report provides an overview of current trials testing the effectiveness of locoregional therapy in combination with immune checkpoint inhibitors and identifies future research goals.     

免疫治疗相关的恶性肿瘤疗效评价标准纵览

免疫检查点抑制剂（ICIs）作为一种新型治疗药物,极大地丰富了癌症的治疗手段,但随之出现的免疫相关反应模式（如假性进展、延迟反应和超进展等）对现行的恶性肿瘤疗效评价标准提出了挑战。因此,研究者对相关的评价标准进行了一些修订,使其能够更客观准确地评价ICIs的治疗效果,以便更科学地指导临床治疗方案的制定。笔者就近年来提出...     

Photodynamic therapy combined with PD-1/PD-L1 blockade immunotherapy: new possibilities for the treatment of immunogenic cancers

The most important features of cancer that limit the effectiveness of current treatments include: i) ability to stimulate angiogenesis; ii) ability to infiltrate surrounding tissues and create distant metastases; iii) ability to escape from the control of the immune system, which under normal conditions prevents tumor progression. The negative immune checkpoints inhibition has become an attractive strategy for cancer treatment. The most common way is the blockade of binding between the programmed death 1 receptor (PD-1) and its ligand PD-L1. However, in order to achieve total therapeutic success, it is crucial to apply a strategy operating in a multiple directions, through various biological mechanisms aimed at complete destruction of the tumor [1-3].Here, we present the design of combining anticancer modality based on photodynamic therapy (PDT) with checkpoint blockade immunotherapy. We developed novel PD-1/PD-L1-targeting molecules and present their therapeutic potential in combination with bacteriochlorin-based PDT. We also compare the results with those obtained with anti-PD-1/PD-L1 mAbs. After comprehensive in vitro screening, we performed PDT augmented by systemic PD-1/PD-L1 inhibition in vivo. Using the multitarget approach it was possible to evaluate whether modulation of inflammatory response induced by PDT affect the tumor microenvironment and determine the susceptibility to systemic PD-1/PD-L1 inhibition including effects on primary tumor control as well as prevention of metastasis in a preclinical model. In summary, our data provide evidence for the role of PDT for local immune modulation, and that the combination with PD-1/PD-L1 checkpoints inhibitors is a promising strategy in the therapy of more resistant tumors [5-6].ACKNOWLEDGEMENTS: We thank National Science Centre (NCN) for grants no 2016/22/E/NZ7/00420 and no 2020/37/B/NZ7/04157.     

PD-1/PD-L1抗体与化学药物治疗眼部不良反应比较的Meta分析

 目的 探讨细胞程序死亡蛋白1(PD-1)及配体(PD-L1)抗体与化学药物治疗(化疗)在眼部免疫相关不良反应上的差异。方法 检索PubMed、EMbase、中英文数据库,时间截止为2019年12月。纳入恶性实体肿瘤采用PD-1/PD-L1抗体治疗与对照组采用化疗比较的临床研究。通过提取关键特征,应用RevMan 5.3对纳入研究进行Meta分析。应用漏斗图对纳入研究的发表偏倚进行评估。结果 PD-1/PD-L1抗体与化疗相比,眼部相关免疫不良反应(1~5级)及严重不良反应(3~5级)发生率差异无统计学意义[OR=1.34,95%CI(0.64~2.80);OR=1.20,95%CI(0.35~4.08)]。漏斗图基本对称分布,偏倚可控。PD-1抗体与化疗相比,眼部相关免疫不良反应(1~5级)及严重不良反应(3~5级)发生率无统计学差异[OR=1.20,95%CI(0.55~2.65);OR=1.00,95%CI(0.26~3.86)]。PD-L1抗体与化疗相比,眼部相关免疫不良反应(1~5级)及严重不良反应(3~5级)发生率无统计学差异[OR=2.82,95%CI(0.29~27.19);OR=2.85,95%CI(0.12~70.15)]。结论 免疫治疗药物PD-1/PD-L1抗体眼部免疫相关不良反应总体发生率、严重程度与化疗相比无统计学差异。     

Checkpoint inhibitors and radiation treatment in Hodgkin’s lymphoma

Background

Patients with classical Hodgkin’s lymphoma (cHL) have a good prognosis even in advanced stages. However, combined chemo- and radiotherapy, as the standard of care, is also associated with treatment-related toxicities such as organ damage, secondary neoplasias, infertility, or fatigue and long-term fatigue. Many patients suffer from this burden although their cHL was cured. Therefore, the efficacy of immune checkpoint inhibitors like anti-PD1/PD-L1 antibodies in the treatment of solid cancers and also in HL offers new options. A remarkable and durable response rate with a favorable toxicity profile was observed in heavily pretreated cHL patients.

Methods

Planning to perform prospective randomized clinical trials in the content of radio-immune treatment in patients with Hodgkin’s lymphoma (HL), we transferred the results of preliminary clinical studies and basic research in clinical relevant study concepts.

Results

Based on these promising early phase trial data, the German Hodgkin Study Group (GHSG) will investigate innovative treatment regimens in upcoming phase II trials.

Conclusion

The therapeutic efficacy and potential synergies of anti-PD1 antibodies in combination with chemo- or radiotherapy will be investigated in various settings of HL.

     

Emerging Trends in the Treatment of Advanced Hepatocellular Carcinoma: A Radiological Perspective

This is a narrative review of various treatment modalities for advanced hepatocellular carcinoma (HCC), with a focus on recent updates in radiological treatments, as well as novel treatment concepts related to immune checkpoint inhibitors and combination therapies with locoregional treatments. Interventional radiologists have made efforts toward developing alternative and/or combination treatments for first-line systemic treatment of patients with advanced HCC. Locoregional treatments with or without systemic therapy may be considered in the selected patients. Various treatment modalities for advanced HCC are emerging, and several randomized controlled trials, including those of combination treatments with immunotherapy, are ongoing.     

肿瘤免疫治疗致甲状腺功能异常的99TcmO4? SPECT显像分析及文献复习

近年来，程序性细胞死亡受体１及其配体的抑制性抗体在恶性肿瘤临床治疗试验中的作用已经得到认同。但此类药物会引发一些不良反应，以甲状腺功能障碍为主的免疫相关不良反应越来越被重视。笔者报道了99TcmO₄? SPECT显像在2例肿瘤免疫治疗后甲状腺功能异常患者中的应用。     

Imaging manifestations of immune-related adverse effects in checkpoint inhibitor therapies: A primer for the radiologist

Immune checkpoint inhibitors are monoclonal antibodies directed against cellular pathways on T-cells to treat different types of malignancies. This new therapy can cause immune-related adverse events that can involve almost any organ system. This article will review clinical presentations, molecular mechanisms and imaging manifestations of adverse events caused by checkpoint inhibitors and also illustrate the pseudoprogression tumor response pattern.     

Neue bildgebende Strategien zum Monitoring molekularer Pharmakotherapien bei GIST

Prognosis and clinical management of patients with gastrointestinal stromal tumors (GIST) has changed significantly with the introduction of new molecular-targeted drugs such as imatinib. This development is accompanied by a need to re-evaluate the established imaging criteria used to assess treatment response. The frequently used response evaluation criteria in solid tumors (RECIST) are mainly based on one-dimensional tumor size and do not take into account functional changes in responding GISTs such as a decrease in CT density or in the number of intratumoral vessels. Positron emission tomography (PET) has been found to be highly sensitive in detecting early response and to have a predictive value in the long term response to imatinib treatment. Monitoring the course of the disease by PET is limited due to scanner availability and economic constraints. Modified CT response criteria using a combination of tumor density and tumor size are especially promising in early response assessment and have a good prognostic value. Further optimization of existing response criteria and evaluation of new candidate markers of treatment response, such as quantitative perfusion will be the key for optimized monitoring of targeted therapies in GIST.     

肺鳞癌PD-L1共表达基因及转录调控网络分析

目的 绘制肺鳞癌中细胞程序性死亡配体1(PD-L1)共表达基因关系网络,筛选潜在的PD-L1协同检测生物标志物,寻找可能参与PD-L1调控肿瘤免疫状态的基因及通路.方法 采用TCGA肺鳞癌数据集,利用cBioPortal数据分析平台进行共表达基因集检索,从全基因转录组水平对PD-L1的共表达基因进行Venny分析,筛选目标基因,进行多种类型的聚类和分子关系网络分析,并建立PD-L1调控网络.结果 共获得PD-L1中等程度表达相关基因126个,主要为质膜定位型基因,功能集中在免疫调节过程,其中IRF2/NFKB 1/IRF1三个转录因子参与了对PD-L1基因集30％以上基因的转录调控.经过PD-L1共表达基因集的核心分子筛选,分析网络节点连接度,得到具有最高连接度的前6个节点基因,依次为IFNG、JAK2、STAT1、CTLA4、CD80和CCR5,对这些基因不同表达水平的肺癌患者的生存情况进行分析,结果显示CCR5是一个有意义的预后指标分子.进一步对PD-L1和CCR5的表达谱数据进行相关性分析,结果显示CCR5与PD-L1表达谱水平的Pearson相关系数为0.47(P＜0.05);GO-BP聚类分析显示,CCR5的功能主要聚集在免疫调控、T细胞调控、细胞信号转导等领域,与PD-L1调控网络的功能相符.结论 PD-L1共表达基因集内的主要节点均为免疫相关分子,其中IFNG、CCR5、NFKB1分子对PD-L1共表达基因网络具有最广泛的调控作用,该发现为肺鳞癌免疫治疗的研究和应用奠定了一定基础.     

Safety and Feasibility of Cryoablation during Immunotherapy in Patients with Metastatic Soft Tissue Sarcoma

PurposePatients with metastatic soft tissue sarcoma (STS) undergo a wide array of treatments, including surgery, radiation, chemotherapy, immunotherapy, and ablative therapies, to control their disease. The combination of cryoablation and immunotherapy may lead to an enhanced antitumor immune response via the abscopal effect. It is hypothesized that the combination of cryoablation and immunotherapy in patients with metastatic STS is safe and feasible.Materials and MethodsA single-center retrospective analysis was performed on patients with metastatic STS who underwent cryoablation. Sixteen patients were treated with 27 cryoablation procedures while receiving ipilimumab and nivolumab from April 2017 to July 2020. Response Evaluation Criteria in Solid Tumors, 1.1, were used to determine the outcomes of nontarget tumors. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the first cryoablation after initiating immunotherapy until progression or death.ResultsThirty-four tumors were cryoablated, 23 of which were intentionally subtotal. The most common tumor subtype was liposarcoma (n = 4). Thirteen (81%) patients had previously demonstrated disease progression on multiple lines of chemotherapy. All tumors cryoablated with a complete intention demonstrated a complete response. Seven patients had a clinical benefit, including 1 with a complete response, 1 with a partial response, and 5 with stable disease. The median OS was 14.1 months, with a median PFS of 2.3 months (95% confidence interval, 1.8–14.3). Five patients had pneumothoraces after cryoablation, 2 of whom required chest tube placement. Eleven patients experienced adverse events related to immunotherapy, 10 of whom experienced grade 1 or 2.ConclusionsCryoablation in patients with metastatic STS undergoing immunotherapy is feasible and safe.     

Evaluating tumor response with FDG PET: updates on PERCIST,comparison with EORTC criteria and clues to future developments

Eighteen years ago, the EORTC PET criteria standardized for the first time response assessment by FDG PET. Response assessment by FDG PET has been further developed and refined by PERCIST (PET response criteria in solid tumors). This review describes the data underlying these two systems for assessing tumor response on FDG PET/CT. It also summarizes recent clinical studies that have compared EORTC criteria and PERCIST with each other as well as with the anatomically based “response criteria in solid tumors” (RECIST). These studies have shown that response assessment by EORTC criteria and PERCIST leads to very similar response classifications. In contrast, there are significant differences between response assessment by PERCIST and RECIST. Preliminary data also suggest that response assessment by PERCIST is better correlated with patient outcome and may be a better predictor for the effectiveness of new anti-cancer therapies than RECIST. If correct, this could have a significant impact on oncologic drug development. However, confirmation of the better predictive value of response assessment by PERCIST by data from randomized trials is still lacking.