Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8⁺ T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H₂O₂, an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31⁺ tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H₂O₂-associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.     

免疫检查点抑制剂对甲状腺功能影响的研究进展

甲状腺功能紊乱(thyroid dysfunction,TD)是癌症患者在接受免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)治疗过程中最常见的内分泌系统免疫相关不良事件(immune related adverse events,IRAEs)之一。本文主要从免疫治疗相关性甲状腺功能紊乱的发病机制、流行病学、诊疗方面、预后展望进行介绍,使更多内分泌科医师和肿瘤科医师认识、掌握免疫治疗相关甲状腺疾病的临床特点和诊疗策略,加强科间合作,以减轻癌症患者免疫抑制剂治疗过程中遭受的甲状腺不良事件带来的影响。     

The efficacy and safety of immunotherapy in thymic epithelial tumors: more effective,more risky: a systematic review

BackgroundThymic epithelial tumors (TETs) are rare malignant neoplasms originating from thymic epithelial cells. The current treatment for localized TETs is surgical removal. However, 20–30% of thymomas and 70–80% of thymic carcinomas are unresectable, recurrent, or metastatic at the time of detection. The standard therapy for these patients is chemotherapy, but the effect is limited. With a deeper understanding of tumor immunity, immunotherapy for various cancers has rapidly developed. Antibodies against cytotoxic T-lymphocyte antigen-4, programmed death-1, and programmed death-ligand 1 have been approved for the treatment of many solid tumors. Compared with traditional treatments, these immune checkpoint inhibitors (ICIs) have better efficacy and lower toxicity. Recently, ICIs have been used more enthusiastically in the treatment of TETs. However, due to the unique biological characteristics of the thymus, immunotherapy usually causes severe immune-related adverse events (irAEs). Most previous studies on immunotherapy in TETs had small sample sizes and reported diverse conclusions.MethodsWe collected relevant studies in PubMed during the last five years and analyzed the available data to discuss the efficacy and safety of ICIs in TETs.ResultsAccording to 14 previous studies in the past five years, all TETs showed expression of programmed death-ligand 1, while thymic carcinomas showed 100% expression. The best median progression-free survival (mPFS) among the five studies was 6.5 months, and the best median overall survival (mOS) was 24.9 months. In addition, the most common irAEs were myasthenic symptoms, liver enzyme elevation, and elevated creatine phosphokinase levels.ConclusionsICIs can be used in TET treatment, especially for thymic carcinomas, in the absence of standard second-line treatment. However, more attention should be paid to irAEs.     

Camrelizumab plus zoledronic acid showed sustained efficacy in a patient with cranial and spinal metastases from lung adenocarcinoma

The role of anti-programmed cell death protein-1 (PD-1) antibody camrelizumab in brain metastases (BMs) from lung adenocarcinoma is uncertain. Herein, for the first time, we report the efficacy of camrelizumab in a patient with chemotherapy-refractory BMs from lung adenocarcinoma. A 49-year-old male non-smoker was admitted with cough and back pain. Primary lung adenocarcinoma with brain and spinal metastases was diagnosed. The specimen from CT-guided lung biopsy showed positive expression of PD-L1 (~20%). The BMs were enlarged after first-line intravenous pemetrexed/cisplatin and zoledronic acid; whereas second-line camrelizumab demonstrated impressive complete remission of the BMs. The intracranial progression-free survival and overall survival of the patient since immunotherapy were more than 12 months and 20 months, respectively. In addition, we searched PubMed for relevant studies from inception to May 2020, and a total of 23 reports enrolling 1187 patients also indicated the promising efficacy of immunotherapy for BMs from lung cancer. However, more and better evidence are still needed before a definite conclusion could be drawn.     

免疫检查点抑制剂在EGFR突变非小细胞肺癌治疗应用的研究进展

目前,表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)是表皮生长因子受体(epidermal growth factor receptor,EGFR)基因敏感突变晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的一线治疗标准,但大多数患者最终出现获得性耐药。而针对免疫检查点程序性死亡受体(programmed death-1,PD-1)及其配体(PD-1 ligand,PD-L1)的抑制剂取得突破性进展,改变了NSCLC的治疗模式。多项研究显示,EGFR敏感突变NSCLC患者免疫检查点抑制剂疗效不佳,其可能机制主要包括EGFR敏感突变患者PD-L1的低表达、抑制性免疫微环境、低肿瘤突变负荷等等。通过对EGFR突变NSCLC患者特殊人群的选择,免疫检查点抑制剂与其他药物的联合应用,可能为EGFR敏感突变NSCLC患者的治疗带来希望。本文将对此进行综述,以期为表皮生长因子受体突变的非小细胞肺癌患者的治疗带来新的希望。     

免疫检查点抑制剂相关结肠炎的诊疗进展

针对抗细胞毒T淋巴细胞相关抗原-4(cytotoxic T-lymphocyte antigen 4,CTLA-4)及程序性死亡受体-1及其配体(pro-grammed cell death 1/programmed cell death-ligand 1,PD-1/PD-L1)的免疫检查点抑制剂(immune che...     

Narrative review: update on immunotherapy and pathological features in patients with bladder cancer

Over the last few years efficacy of immunotherapy using immune checkpoint inhibitors (ICI) has been investigated in patients with bladder cancer (BC) at all stages. The present article aims to assess new therapeutic options with emerging agents in BC patients, shedding light on ICI-based treatments encompassing all disease stages, from non-muscle invasive (NMIBC) to muscle-invasive (MIBC) BC, concluding with metastatic MIBC. In bacillus Calmette-Guerin (BCG) unresponsive patients with carcinoma in situ, pembrolizumab has been recently approved. In the neoadjuvant setting, results from two clinical trials seem to identify pathological and genomic features of highly responsive tumors. Squamous cells and lymphoepithelioma/like histotypes, programmed cell-death ligand 1 (PD-L1) expression and high levels of activate T cells have been associated with higher response rate. In the metastatic setting, only 30% of patient may respond to ICI. A panel of biomarkers for patient selection is an actual need since the correlation between response and PD-L1 expression seem inconsistent across clinical trials, with some exceptions. Molecular characterization of BC, tumor mutation burden and immune-gene expression profiling might introduce new molecular biomarkers, hopefully transferable into the clinical-pathological practice.     

VISTA靶点肿瘤免疫治疗的研究进展

T细胞激活抑制物免疫球蛋白可变区结构域（VISTA）是维持T细胞和髓系细胞稳态的B7家族成员。在体外和体内试验中，阻断VISTA能抑制肿瘤发展，是肿瘤联合免疫治疗的重要靶点。本文介绍了免疫检查点（ICIs）VISTA的结构特征以及在肿瘤微环境中的表达和生物学功能，总结了目前靶向VISTA的小分子抑制剂和中和抗体的最新研究现状，对目前的研究方法进行了讨论，旨在为VISTA后续研究和相关免疫检查点抗肿瘤药物研发提供理论参考。