Development and validation of a risk-prediction model for immune-related adverse events in patients with non-small-cell lung cancer receiving PD-1/PD-L1 inhibitors / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.

Efficacy and safety of PD-1/PD-L1 inhibitors-based immunocombination therapy versus sunitinib in the treatment of advanced renal cell carcinoma: a Meta-analysis / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：系统评价基于PD-1/PD-L1抑制剂的免疫联合治疗（以下称“免疫联合治疗”）对比舒尼替尼治疗晚期肾细胞癌（RCC）的安全性和有效性。方法：检索PubMed、Embase、Cochrane Library及中国知网（CNKI）数据库，收集国内外公开发表的免疫联合治疗对比舒尼替尼应用于晚期RCC的随机对照试验（RCT），检索时间均为自建库时间至2022年10月。由两名研究者独立评价纳入研究的质量、提取资料并交叉核对，采用StataMP16.0软件进行Meta分析。结果：共纳入6项RCT，Meta分析结果显示，（1）有效性：与舒尼替尼相比，免疫联合治疗显著提高了晚期RCC患者的总生存期[OS，HR=0.74，95% CI （0.67，0.80），P<0.01]和无进展生存期[PFS，HR=0.66，95% CI （0.51，0.81），P<0.01]；（2）安全性：两治疗组均有较高的不良反应（AE）发生率，差异无统计学意义。但免疫联合治疗组发生皮肤及内分泌系统AE显著高于舒尼替尼治疗组，而血液系统相关AE则明显低于舒尼替尼治疗组；（3）以1%为临界点，免疫联合治疗组的RCC患者，无论是PD-L1阳性或阴性的，其OS和PFS均高于舒尼替尼组。结论：免疫联合治疗可显著延长晚期RCC患者的OS和PFS，但不同系统发生AE有差异，且RCC患者PD-L1表达状态（1%为临界点）并不影响免疫联合治疗的获益。

TumorFisher CTC detection technology for the treatment decision of anti-PD-1/PD-L1 in advanced hepatocellular carcinoma and its efficacy evaluation：a case report and literature review / 中国肿瘤生物治疗杂志

@#[摘 要] 肝细胞癌（HCC）的发病率和病死率正在逐年增长，严重威胁人类的健康和生命。近年来，以PD-1/PD-L1抑制剂为代表的免疫治疗迅速发展，但对晚期HCC疗效有限。治疗中实时监测循环肿瘤细胞（CTC）PD-L1表达，是评估免疫治疗有效性的重要指标之一。本案例通过TumorFisher检测技术实时监测1例HCC患者免疫治疗前后总CTC数及PD-L1+ CTC个数，结合影像学和血清学检查结果进一步评估患者免疫治疗疗效。患者治疗前总CTC数为5个/2 mL，PD-L1+ CTC为5个/2 mL，PD-L1+ CTC/总CTC为100%。用PD-1/PD-L1抑制剂行3周期免疫治疗后，PD-L1+ CTC/总CTC逐渐降低，肿瘤缩小，血清AFP及PIVKA-Ⅱ逐渐下降，PD-L1+ CTC/总CTC变化与肿瘤标志物、MRI检查结果一致。PD-L1+ CTC/总CTC可作为HCC免疫治疗疗效评估的辅助指标。

PD-1/PD-L1 inhibitors for breast cancer: current status, problems and countermeasures / 中国肿瘤生物治疗杂志

@#[摘 要] PD-1/PD-L1抑制剂在乳腺癌免疫治疗中的应用已逐渐成为一种重要的治疗手段，然而对乳腺癌，尤其是三阴性乳腺癌（TNBC）的免疫治疗仍存在某些亟待解决的科学问题，包括PD-1/PD-L1抑制剂单药治疗的有效率欠佳，目前尚无明确的生物标志物来有效筛查治疗敏感人群，免疫相关不良反应（irAE）的发生率高。为了提高疗效和减少irAE的发生，采取以下措施是非常重要的：探讨PD-1/PD-L1抑制剂与其他药物的联合应用方案；采用纳米技术开发选择性靶向肿瘤细胞的纳米载体，降低抗肿瘤药物毒性并提高疗效；探寻开发可预测免疫治疗反应潜力的生物标志物；早期识别和诊疗irAE并建设多学科诊疗协作组（MDT）模式。随着这些措施的积极推进和问题的不断解决，PD-1/PD-L1抑制剂在乳腺癌的治疗中必将呈现出更为广阔的应用前景。

Progress on application of PD⁃1／PD⁃L1 monoclonal antibodies in oncotherapy / 中国生物制品学杂志

@#Abstract：Programmed death receptor⁃ 1（PD⁃1）belongs to the family of immunoglobulin B7⁃CD28，which plays an important role in regulating immune response in human body. Since the first PD⁃1／PD⁃ligand 1（PD⁃L1）monoclonal antibody was approved for marketing in China in 2018，the value of PD⁃1／PD⁃L1 immunotherapy in oncotherapy has attracted wide attention. Based on the introduction of the action mechanism of PD⁃1／PD⁃L1 mAbs，this paper reviews the application progress of 8 on ⁃ market PD ⁃ 1／PD ⁃ L1 mAbs in China in oncotherapy from the perspectives of approved indications，clinical trials，usage and dosage，and adverse reactions，in order to provide reference for the rational appli⁃ cation of PD⁃1／PD⁃L1 monoclonal antibodies in clinic.

Progress of Research on Programmed Death-1/Programmed Death Ligand-1 Inhibitors for HIV/AIDS with Cancer / 肿瘤防治研究

Immunotherapy has become a common means of cancer treatment. In immunotherapy, PD-1/PD-L1 inhibitors have significant efficacy. Cancer and various opportunistic infections are common complications in patients with AIDS. Owing to the special immune situation of these patients, AIDS is regarded as an exclusion standard in most clinical trials for cancer immunotherapy, conferring immunotherapy difficulty in treating patients with AIDS. The popularity of effective antiretroviral drugs has prolonged the lifetime of people with AIDS. Therefore, exploiting the opportunity of using immunotherapy in AIDS with cancer is urgent.

Prospect of Tumor Treatment in the Post-PD-1/PD-L1 Inhibitor Era / 肿瘤防治研究

Immune checkpoint inhibitors restart and maintain cancer-immunity circulation to normalize the anti-tumor immunity. Currently, anti-PD-1/PD-L1 antibodies, as new milestone in immunotherapy, have significantly improved the prognosis of patients with various malignant tumors. However, anti-PD-1/PD-L1 antibody alone exhibited a low response rate, and the combination of anti-PD-1/PD-L1 antibody with traditional therapies such as surgery, chemotherapy, radiotherapy and targeted therapy have shown great potential. As new immune checkpoint inhibitors or in combination therapy are on the way, tumor immunotherapy is entering the era of post-anti-PD-1/PD-L1 antibody. The methodology of combination therapy and biomarker screening remain the focus. This paper reviews the current status of immune checkpoint inhibitor therapy and makes a perspective for the future of post-anti-PD-1/PD-L1 antibody era.

The effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B cells and CD4+T cells in peripheral blood of patients with systemic lupus erythematosus

Abstract Background The defect of B cell self-tolerance and the continuous antigen presentation by T cells (TCs) mediated by autoreactive B cells (BCs) play a key role in the occurrence and development of systemic lupus erythematosus (SLE). PD-1/PD-L1 signaling axis negatively regulates the immune response of TCs after activation and maintains immune tolerance. However, the effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B/CD4+TCs in the peripheral blood of patients with SLE has not been studied in detail. Methods PD-1/PD-L1 and Ki-67 levels in peripheral blood (PB) of 50 SLE patients and 41 healthy controls (HCs) were detected through flow cytometry, and then the expression of PD-1+/−cells and PD-L1+/−cells Ki-67 was further analyzed. CD19+B/CD4+TCs were separated for cell culture and the supernatant was collected to determine proliferation and differentiation of TCs. IL-10 and IFN-γ secretion in the supernatant was also determined using ELISA. Results The PD-1, PD-L1, and Ki-67 levels on CD19+B/CD4+TCs in patients with SLE were higher than HCs. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ cells was higher than that of PD-L1− cells, and the proliferative activity of PD-1+ cells was higher than that of PD-1− cells. In the system co-culturing CD19+B/CD4+TCs from HCs/SLE patients, activated BCs promoted TCs proliferation and PD-L1 expression among TCs. Addition of anti-PD-L1 to co-culture system restored the proliferation of TCs, and inhibited IL-10/IFN-γ level. The addition of anti-PD-L1 to co-culture system also restored Tfh and downregulated Treg in HCs. Conclusions Axis of PD-1/PD-L1 on CD19+B/CD4+TCs in PB of SLE patients is abnormal, and cell proliferation is abnormal. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ and PD-1+ cells compared with PD-L1− and PD-1− cells in SLE patients, respectively. CD19+B/CD4+TCs in SLE patients can interact through PD-1/PD-L1.

Immunotherapy in the treatment of chemoresistant gestational trophoblastic neoplasia - systematic review with a presentation of the first 4 Brazilian cases

Abstract Objective To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. Methods Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. Results Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. Conclusion Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.

Research progress on the correlation between dermatological immune-related adverse events and clinical outcome of PD-1/PD-L1 inhibitors / 国际肿瘤学杂志

Immunotherapy represented by PD-1/PD-L1 inhibitors has become the main treatment of malignant tumors. However, the adverse events caused by immunotherapy can not be ignored. Among them, dermatological immune-related adverse events (irAEs) occur with the highest incidence. Most dermatological irAEs belong to grade Ⅰ-Ⅱ, which does not affect the application of PD-1/PD-L1 inhibitors. The pathogenesis of dermatological irAEs is not fully understood. The most common types of dermatological irAEs are rash, pruritus and vitiligo. The domestic PD-1 inhibitor camrelizumab has unique adverse reactions of reactive cutaneous capillary endothelia proliferation (RCCEP) . It is found that dermatological irAEs can predict the clinical efficacy of PD-1/PD-L1 inhibitors in patients with malignant melanoma and non-small cell lung cancer (NSCLC) , especially RCCEP can be used as a potential biomarker of the efficacy of camrelizumab in the treatment of NSCLC, hepatocarcinoma, and esophageal cancer.

Biomarkers for evaluating the prognosis of non-small cell lung cancer treated with immune checkpoint inhibitors / 中国肿瘤生物治疗杂志

@#[摘 要] 免疫检查点抑制剂（ICI）是一种备受关注的肿瘤免疫治疗手段，可通过阻断免疫检查点信号转导来恢复甚至增强T淋巴细胞的抗肿瘤免疫反应以达到抗肿瘤的治疗目的。PD-L1表达水平或可作为派姆单抗的一线使用标准；较高的肿瘤突变负荷（TMB）增加癌细胞抗原表达，使后者易被免疫细胞监视定位并清除，被定义为预测ICI疗效的生物标志物；错配修复基因（MMR）与MSI具有高度一致性，在多种实体瘤中具有预后预测作用；肿瘤浸润淋巴细胞联合TNM分期评估非小细胞肺癌患者预后准确性甚至优于病理标准，通过检测炎症因子的基因表达水平评估T细胞炎症基因表达谱可预测ICI的治疗效果；体细胞突变状态与免疫治疗的预后有关；低水平的中性/淋巴细胞比值（NLR）可能是免疫相关不良事件发生的独立预测因素；肠道微生物通过影响TIL水平干预免疫治疗的效果；除此以外还有其他预测因素可供参考。梳理总结预测相关标志物，分析其价值性与局限性，可为临床选择适合患者的治疗方案，也可使患者临床获益达到最大。

Real-world study evaluating the incidence of liver damage conditions in patients with primary liver cancer using immune checkpoint inhibitor-based combination therapy / 中华肝脏病杂志

Objective: To evaluate the incidence of immune checkpoint inhibitor-based combination therapy-induced liver damage in patients with primary liver cancer. Methods: Clinical data of 65 hospitalized cases of primary liver cancer treated with programmed cell death-1 its ligand programmed death-ligand 1 (PD-1/PD-L1) antibody in the Department of Infectious Diseases of the Second Affiliated Hospital of Chongqing Medical University from January 1, 2018 to March 31, 2021 were retrospectively analyzed. The degree of liver injury before and after treatment was assessed according to CTCAE v5.0. Patients were grouped according to gender, age, presence or absence of cirrhosis, baseline Child-Pugh score, BCLC stage, and treatment regimen to compare the incidence of liver injury under different conditions. The χ (2) test or rank-sum test was used for comparison among multiple groups. Results: 46 cases (70.77%) had liver damage of any grade according to the CTCAE V5.0 criteria during the treatment and observation period. All 6 cases who received standardized anti-hepatitis B virus (HBV) treatment developed liver damage. 10 (15.38%), 15 (23.08%), 19 (29.23%), and 2 (3.08%) cases had grade 1, 2, 3, and 4 liver damage respectively. There was no statistically significant difference in the incidence of liver damage between male and female patients (68.33% and 100%, P = 0.180). There was no statistically significant difference in the incidence of liver damage among different age groups (P = 0.245). The incidence of liver damage in cirrhotic and non-cirrhotic group was 72.22%, and 63.64% (P = 0.370), respectively. The incidence of liver damage in patients with baseline Child-Pugh class A, B, and C were 71.43%, 61.11% and 100%, respectively, and the difference was not statistically significant (P = 0.878). The incidence of liver damage was not statistically significantly different under different BCLC stages (P = 1.000). The incidence of liver damage in the PD-1/PD-L1 antibody monotherapy, PD-1/PD-L1 antibody combined with targeted drug therapy, and PD-1/PD-L1 antibody combined with TACE/radiofrequency ablation treatment group were 60.00%, 67.85%, and 86.67%, respectively. There was no statistically significant difference in the incidence of liver damage between the treatment regimen (P = 0.480). Conclusion: Immune checkpoint inhibitor therapy-induced liver damage is common in patients with primary liver cancer; however, it rarely severely endangers the patient's life. Additionally, patient's gender, age, presence or absence of cirrhosis, baseline liver function, BCLC stage and the immunotherapy regimen has no effect on the incidence of immune-related liver damage.

Characteristics and clinical significance of the changes in PD-1/PD-L1 and related immune cells in peripheral blood and tumor tissues of patients with cervical squamous cell cancer / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨PD-1/PD-L1通路及相关免疫细胞在宫颈鳞癌（cervical squamous cell cancer，CSCC）发生、发展中的变化特点及其临床意义。方法：收集2018年12月至2020年9月在福州市第一医院接受手术的CSCC患者和健康体检人员的癌组织/宫颈组织和外周血样本，分为健康对照组、宫颈上皮内癌变（cervical intraepithelial neoplasia，CIN）Ⅱ级组、CIN Ⅲ级组和CSCC组，代表CSCC发生、发展进程各阶段，每组50例。ELISA法检测各组人员的外周血血浆中PD-1、PD-L1、叉头状转录因子P3（FOXP3）的表达水平，FCM法检测各组人员外周血PD-1+CD4+CD25+CD127-/low细胞的数量，应用多色荧光组织染色法检测肿瘤浸润性淋巴细胞（TIL）在CSCC组织中的分布特点。结果：随着模拟的CSCC发生和发展，外周血中PD-1、PD-L1和FOXP3 的表达呈上升趋势，术后则呈下降趋势。在CSCC患者抗凝全血中，CD4+、CD4+CD25+CD127-/low以及PD-1+CD4+CD25+CD127-/low细胞占淋巴细胞的比例增加。在CSCC组织中可见大量CD4+、CD8+和FOXP3+细胞浸润，其中CD4+和FOXP3+细胞主要围绕肿瘤细胞聚集区分布、CD8+和PD-L1+细胞则呈广泛弥漫性分布。结论：PD-1、PD-L1、FOXP3和适应性调节性T细胞是促进CSCC发生发展的重要因素，其可作为ESCC免疫治疗的靶点和临床预后的潜在标志物。

Effect of Rapamycin on Exosomes and PD-1/PD-L1 in Human Erythroleukemia HEL Cells / 肿瘤防治研究

Objective To determine the effect of rapamycin(Rapa) on JAK2, ABCA3, and the immune checkpoint PD-1/PD-L1 in exosomes derived from JAK2 V617F positive HEL cells. Methods Human erythroleukemia HEL cells (JAK2 V617F mutation-positive) were cultured in vitro, and rapamycin was added at concentrations of 10, 50, and 100 nmol/L. The control group was established and cell proliferation inhibition rate was detected by CCK-8. Based on the inhibition rate of cell proliferation, cells intervened with 10 and 50 nmol/L Rapa were selected. Exosomes were extracted using a kit and identified by Western blot and flow cytometry. JAK2, ABCA3, and PD-1/PD-L1 mRNA changes in exosomes were detected by fluorescent quantitative PCR. The expression of exosome PD-1/PD-L1 protein was determined by flow cytometry. Results The exosomes extracted with the exosome kit all expressed characteristic CD9, CD63, and CD81 proteins, which were consistent with the general characteristics of exosomes. JAK2 mRNA can be detected in exosomes from HEL cells; Rapa reduced exosome production by HEL cells, and dose-dependently decreased gene expression of JAK2, ABCA3, and PD-L1 in exosomes. In addition, Rapa inhibited exosomal PD-L1 protein expression and had no significant effect on PD-1 protein expression. Conclusion HEL cells may transmit JAK2 mutant gene signals via exosomes. Rapa can reduce the production of exosomes and inhibits JAK2 mutated signals delivered by exosomes and suppresses PD-L1 protein expression.

Research Progress of PD-1/PD-L1 Inhibitor Combined with Trastuzumab in HER2-positive Breast Cancer / 肿瘤防治研究

HER2 gene is expressed in 20%-30% of breast cancer patients, and HER2 expression provides a new direction for treatment. However, breast cancer with positive HER2 still has a poor prognosis and is prone to recurrence and metastasis. Trastuzumab is a classic basic drug for anti-HER2 therapy. However, the problem of primary and acquired drug resistance of trastuzumab has attracted people's attention. Studies have found that the occurrence of insensitive and drug resistance mechanism is related to PD-L1 up-regulation on tumor cell surface. Therefore, a large number of studies on PD-1/PD-L1 inhibitor combined with trastuzumab were carried out to improve its sensitivity and drug resistance. This article reviews the preclinical and clinical studies on PD-1/PD-L1 inhibitors in breast cancer with positive HER2.

Systematic Analysis of Economic Evaluation of Listed PD- 1/PD-L1 Inhibitors in China / 中国药房

OBJECTIVE：To provide reference for the selection of more economical programmed death- 1（PD-1）/programmed death-ligand 1（PD-L1）inhibitors for National Medical Insurance List and the quality improvement of related economic evaluation. METHODS：Retrieved from CNKI ，VIP，Wanfang database ，PubMed，Web of Science and Ovid Embase ，economic evaluation studies including listed PD- 1/PD-L1 inhibitors of China were collected during the inception to Oct. 2020. CHEERS checklist was used to evaluate the quality of the included literatures ，and the methodological characteristics and economic evaluation results of the included studies were analyzed systematically. RESULTS ：A total of 14 literatures were included ，all of which were model-based and with moderate or high quality. However ，there were still some deficiencies in the included literatures ，mainly manifesting as the insufficient reports on the reasons for setting or selecting model parameters ，as well as the great uncertainty of clinical effect data and utility value. Only 3 of the 8 PD-1/PD-L1 inhibitors listed in China were involved in the included literatures. Compared with chemotherapy or targeted therapy plan ，9 literatures（64.29％）showed that the therapy plan containing PD- 1/PD-L1 inhibitors was not cost-effective. CONCLUSIONS ：The economic evidence of domestic PD- 1/PD-L1 inhibitors is lacking ，the higher price of imported PD- 1/PD-L1 inhibitors lead to poor economic performance. The existing economic evaluations has some shortcomings in methodological application and parameter selection. Pharmaceutical enterprises should fill in the data gaps and adjust the pricing strategy，researchers should improve the standardization of research ，and medical insurance decision-making departments should improve the judgment on the quality of economic evidences ，so as to promote more economical drugs to be included in the National Medical Insurance List.

A new dimeric benzylisoquinoline alkaloid from Corydalis yanhusuo / 药学学报

(±)-Bicoryanhunine B (1), a new dimeric benzylisoquinoline alkaloid was isolated from the dried tubers of Corydalis yanhusuo by various chromatographic methods, including silica gel, Sephadex LH-20, reverse phase C18, and semi-preparative HPLC. Its structure was determined by spectroscopic methods, including UV, IR, ESI-MS, HR-ESI-MS and 1D/2D NMR. (±)-Bicoryanhunine B (1) was a moderate PD-1/PD-L1 interaction inhibitor with an IC50 value of 7.80 ± 0.49 μmol·L-1. In addition, 1 exhibited potent inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages with an IC50 value of 4.83 ± 2.21 μmol·L-1.

Correlation between PD-L1 and Tregs in tumor immunity and immunotherapy / 国际肿瘤学杂志

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are important co-inhibitory molecules, while regulatory T cells (Tregs) are important suppressor cells. The increase of them in tumor microenvironment is closely related to tumor immune escape and tumor development. PD-L1 plays an important role in the development and function of Tregs. The application of PD-1/PD-L1 blockade also affects the proliferation and function of Tregs, which further participates in the occurrence of drug resistance and hyperprogressive disease. Further understanding of the role and correlation of PD-L1 and Tregs in tumor immunity and immunotherapy can provide new ideas for improving the efficacy of PD-1/PD-L1 blockade.

Progress in clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of hepatocellular carcinoma / 中国肿瘤生物治疗杂志

@#［摘要］ PD-1/PD-L1 免疫检查点抑制剂（ICI）在单药或联合治疗肝细胞癌（HCC）的临床试验显示出较好的疗效和安全 性，为其临床应用提供有利的科学依据。单药治疗HCC 的PD-1/PD-L1 ICI 包括纳武利尤单抗（nivolumab）、帕博利珠单抗 （pembrolizumab）和卡瑞利珠单抗（camrelizumab），主要用于肝癌的二线治疗。虽部分HCC 患者可以对PD-1/PD-L1 ICI 单药 治疗产生持久的反应，但总体受益的患者仍然较少。PD-1/D-L1 ICI 联合治疗显示出更好的免疫应答和控制。目前，常用的 联合治疗手段包括与其他类ICI、靶向药物、放疗、化疗以及介入治疗等联合。与双ICI 或ICI 和化疗联合治疗相比，酪氨酸激 酶抑制剂（TKI）和PD-1/PD-L1 ICI 联合治疗显示出更好的疗效。在安全性方面，联合治疗的不良反应发生率发也高于单药 治疗，且更易出现严重或致死性的不良反应。PD-1/PD-L1 ICI 单药和联合治疗HBV/HCV 相关HCC 患者的安全性和有效性 正在研究中，同时接受抗病毒药物治疗患者表现出稳定的治疗应答，但HBV/HCV 病毒重新激活相关的安全性问题，尚未得 出一致结论。

The functions of co-signaling molecules and their clinical applications in cancer therapy / 中国肿瘤生物治疗杂志

@#[摘 要] B7/CD28家族分子作为主要的共信号分子，在T细胞功能调控及免疫应答中发挥着至关重要的作用，关于其功能的研究及应用在世界范围内广泛开展。其中，CD28和CTLA-4都可以与B7-1/B7-2结合，但CD28能够促进T细胞增殖，维持Treg细胞稳态；而CTLA-4则可以抑制T细胞增殖，影响CD4+T细胞的分化；抗CTLA-4单抗ipilimumab与抗PD-1单抗联用能够用于治疗PD-L1+的非小细胞肺癌以及无症状的Ⅳ期黑色素瘤。PD-L1/PD-L2：PD-1途径则可以通过多种方式调节T细胞功能，参与CD8+T细胞“耗竭”状态的形成与维持。目前，针对PD-L1/PD-L2：PD-1途径的免疫治疗相关药物开发广泛且较为成熟，抗PD-1单抗主要通过诱导肿瘤浸润的部分耗竭的CD8+T细胞亚群的扩增发挥抗肿瘤作用。ICOS：ICOSL途径在T细胞分化、细胞因子分泌以及体液免疫应答中起着重要作用，抗ICOS抗体药物feladilimab与抗PD-1单抗联用能够有效治疗多发性或难治性骨髓瘤。B7-H3同时具有共刺激效应和共抑制效应，阻断B7-H3后能够有效增强TIL的抗肿瘤效应，其单抗enoblituzumab能够与抗PD-1单抗联用治疗非小细胞肺癌。B7-H4、人内源性逆转录病毒‑H长末端重复关联蛋白（human endogenous retrovirus‑H long terminal repeat‑associating protein，HHLA）以及含V结构域抑制T细胞活化的免疫球蛋白（V‑domain Ig‑cotaining suppressor of T cell activation，VISTA）均能够提供抑制信号，针对B7-H4靶点的CAR-T治疗以及VISTA的小分子抑制剂CA-170均有临床试验正在进行中。目前，对共信号分子的研究已经获得了长足进展，针对某些活化性分子或者抑制性分子开发了相关抗肿瘤药物并在临床中取得一定成效，但如何进一步提高其治疗有效率、减少不良反应等仍有待探索。