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Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

World Journal of Gastroenterology 2018年第17期24卷 1839-1858页

作者： Naofumi Mukaida Yasunari Nakamoto Division of Molecular Bioregulation Cancer Research Institute Kanazawa University Second Department of Internal Medicine Faculty of Medical Sciences University of Fukui

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

关键词： natural killer T cell natural killer cell chimeric antigen receptor T cell T cell receptor cytokine-induced killer cell program death-1 cytotoxic lymphocyte antigen-4 regulatory T cell dendritic cell myeloid-derived suppressor cell PD-ligand 1 peptide vaccine tumor-associated antigen tumor infiltrating lymphocyte

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Immune blockade inhibitors and the radiation abscopal effect in gastrointestinal cancers

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World Journal of Gastrointestinal Oncology 2018年第9期10卷 221-227页

作者： Ioannis A Voutsadakis Algoma District Cancer Program Sault Area Hospital Section of Internal Medicine Division of Clinical SciencesNorthern Ontario School of Medicine

The field of tumor immunology has produced in the recent years a revolution in cancer therapeutics putting an end in the long lasting frustration of investigators in the area stemming from largely unsuccessful strides to develop cancer vaccines. This progress has come from the introduction of immune checkpoint inhibitors, monoclonal antibodies blocking ligand/receptor pairs with inhibitory effects for immune cells. Through this blockade immune checkpoint blockers are able to ac-tivate the immune system and create an anti-tumoral effect. A significant sub-set of patients with various types of cancers such as melanoma, lung carcinomas and urothelial cancers benefit from treatment with these drugs and survivals have improved in some ca-ses. However other cancers are primarily resistant to immune blockers and secondary resistance is also the norm. Radiation therapy is often used in the palliative treatment of patients with advanced cancers and, in addition to the local effect in the irradiated field, it may in rare cases produce a systemic antitumor effect, termed "abscopal". This effect has been suggested to be produced by immune mechanisms. Thus an opportunity presents for a synergistic effect of immune stimulation between radiation and immune blockade inhibitors. The therapeutic opportunities presented with the combination of radiation and these drugs for gastrointestinal cancers will be discussed in this editorial overview.

关键词： Abscopal effect Radiation CD28/cytotoxic T-lymphocyte antigen-4 Immune blockade inhibitors Programmed death 1 Programmed death ligand-1

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Targeted immunotherapy for non-small cell lung cancer

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World Journal of Clinical Oncology 2014年第2期5卷 39-47页

作者： Monali Vasekar Xin Liu Hong Zheng Chandra P Belani Penn State Hershey Cancer Institute Penn State University College of Medicine

Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer(NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.

关键词： Immunotherapy Non-small cell lung cancer Programmed death-1 Programmed death ligands 1 Cytotoxic T-Lymphocyte antigen-4

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Immunotherapy in pancreatic cancer:Unleash its potential through novel combinations

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World Journal of Clinical Oncology 2017年第3期8卷 230-240页

作者： Songchuan Guo Merly Contratto George Miller Lawrence Leichman Jennifer Wu Division of Hematology and Oncology Perlmutter Cancer CenterNew York University School of Medicine

Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall *** that target cytotoxic T lymphocyte antigen-4,programmed cell death protein-1,and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma,renal cell carcinoma,and nonsmall cell lung cancer due to high numbers of somatic mutations,combined with cytotoxic T-cell ***,single checkpoint blockade was ineffective in pancreatic cancer,highlighting the challenges including the poor antigenicity,a dense desmoplastic stroma,and a largely immunosuppressive *** this review,we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy,radiotherapy,and targeted *** combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.

关键词： Immunotherapy Pancreatic cancer Antiprogrammed cell death protein-1 Anti-programmed cell death protein-ligand1 Anti-cytotoxic T lymphocyte antigen-4 Single therapy Combination therapies Radiation therapy GVAX CRS-207 CD40 agonist

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Cancer immunotherapy for hepatocellular carcinoma

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Hepatoma Research 2018年第9期4卷 1-18页

作者： Joo-Ho Lee Soo-Yeon Oh Jin Yong Kim Naoshi Nishida Department of Gastroenterology and Hepatology CHA Bundang Medical CenterCHA University School of MedicineSeongnam 13496South Korea Department of Gastroenterology Chaum Life CenterCHA University School of MedicineSeoul 06062South Korea Department of Gastroenterology and Hepatology Kindai University Faculty of MedicineOsaka-Sayama 589-8511Japan

Most hepatocellular carcinomas (HCCs) arise on a background of chronically inflamed liver, and thus are considered typical immunogenic cancers. Although there have been advances in treatment options for HCC, many patients still struggle with a limited chance of survival requiring further innovative approach. Especially for the advanced HCC, many other molecular targeted therapies had been evaluated without success. Based on the immunological mechanisms thought to be acting during HCC development, the effects of diverse immunomodulatory regimens such as therapeutic vaccination, immune checkpoint inhibitors, and adoptive cellular immunotherapy have been investigated. Notably, many strategies have been developed in adoptive cellular immunotherapy, including dendritic cells, cytotoxic T cells, natural killer cells, cytokine-induced killer (CIK) cells, and genetically engineered T cells. In recent clinical trials, adjuvant CIK cell immunotherapy increased progression free survival after curative treatment of HCC. Most recently, new immunomodulatory agents were introduced for oncological treatment, eventually leading to the clinical breakthrough of checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). To date, very promising published evidence with checkpoint inhibitors in HCC has been reported in the clinical trials with anti-CTLA-4 agent tremelimumab and a large phase II trial with anti-PD-1 agent nivolumab. Further investigations of immuno-oncology potentially popularized the applications of immunotherapy in the various stages of HCCs, and thus immune-based therapies are the promising innovative approach for patients with HCC. Hopefully, the immuno-oncology will bring about a paradigm shift of anti-cancer treatment for HCC.

关键词： Hepatocellular carcinoma adoptive immunotherapy cytotoxic T lymphocyte associated antigen-4 programmed cell death 1 protein

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Diarrhoea in a patient with metastatic melanoma:Ipilimumab ileocolitis treated with infliximab

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2013年第3期4卷 80-82页

作者： Rob ME Slangen Alfonsus JM van den Eertwegh Adriaan A van Bodegraven Nanne KH de Boer Department of Gastroenterology and Hepatology HagaZiekenhuis2545 CH Den HaagThe Netherlands Department of Medical Oncology VU University Medical Centre1007 MB AmsterdamThe Netherlands Department of Gastroenterology and Hepatology VU University Medical Centre1007 MB AmsterdamThe Netherlands

Administration of ipilimumab,a cytotoxic T-lymphocyte associated antigen-4-blocking monoclonal antibody,leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma *** patients are currently receiving this promising therapy as a secondline ***,by activation of the T-cell immune reponse,ipilimumab therapy may lead to an unwanted induction of different autoimmune *** and colitis occur in up to one third of *** we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab,an anti-tumor necrosis factor monoclonal antibody,after corticosteroid therapy *** formal trials are lacking,recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis.

关键词： Melanoma Ipilimumab Colitis Infliximab Cytotoxic T-lymphocyte associated antigen-4

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初发1型糖尿病患儿外周血单个核细胞FOXP3和CTLA-4表达的研究

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中国小儿急救医学 2016年第12期23卷 838-841页

作者：曹婷辛颖中国医科大学附属盛京医院儿科沈阳110004

目的：研究初发1型糖尿病患儿外周血叉状头转录因子（ FOXP3）和细胞毒性T细胞相关抗原-4（CTLA-4）表达水平,探讨它们在1型糖尿病发病中的作用。方法选取50例初发1型糖尿病患儿和30例健康儿童,采用real-time PCR法研究FOXP3和CTLA-4 m... 详细信息

目的：研究初发1型糖尿病患儿外周血叉状头转录因子（ FOXP3）和细胞毒性T细胞相关抗原-4（CTLA-4）表达水平,探讨它们在1型糖尿病发病中的作用。方法选取50例初发1型糖尿病患儿和30例健康儿童,采用real-time PCR法研究FOXP3和CTLA-4 mRNA表达；ELISA方法检测血清中可溶性FOXP3（ sFOXP3）和CTLA-4（ sCTLA-4）蛋白水平；分别应用免疫印记法、高效液相离子层析法和电化学发光法测量糖尿病抗体、HbA1C及C肽。结果1型糖尿病患儿FOXP3 mRNA及蛋白表达低于对照组[0.95±0.48 vs.2.11±0.79,（6.27±1.49） ng/ml vs.（9.02±2.37） ng/ml,均P〈0.01],而CTLA-4 mRNA及蛋白表达高于对照组[2.43±0.83 vs.1.94±0.84,（77.88±22.34） ng/ml vs.（65.97±12.11） ng/ml,P〈0.01]；1型糖尿病患儿FOXP3和CTLA-4基因与蛋白表达均呈正相关（r＝0.758、0.396,均P〈0.05）；FOXP3与CTLA-4蛋白表达具有相关性（r＝－0.624,P〈0.05）。结论初发1型糖尿病患儿外周血FOXP3和CTLA-4的基因及蛋白表达异常,FOXP3调控CTLA-4在调节性T 细胞的表达,提示免疫机制参与1型糖尿病的发生。

关键词： 1型糖尿病调节性T细胞叉状头转录因子细胞毒T细胞相关抗原-4 Foxhead transcription factor-3 Cytotoxic T-lymphocyte antigen-4

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Costimulatory blockade:A novel approach to the treatment of glomerular disease?

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World Journal of Methodology 2015年第2期5卷 20-25页

作者： Pasquale Esposito Teresa Rampino Antonio Dal Canton Department of Nephrology Dialysis and TransplantationFondazione IRCCS Policlinico San Matteo and University of Pavia

Costimulatory pathways(Cluster of differentiation 28,tumor necrosis factor-related,adhesion and T Cell Ig-and mucin-domain molecules) regulating the interactions between receptors on the T cells andtheir ligands expressed on several cell types,have a key role in controlling many immunological and non immunological ***,accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions,such as allograft rejection,atherosclerosis,rheumatoid arthritis,psoriasis and renal diseases,including *** or secondary(i.e.,associated with infections,drugs or systemic diseases,such as systemic lupus erythematosus,diabetes,etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic *** costimulatory molecules,in particular CD80 and CD40,have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis,costimulation has been thought as a new therapeutic target for patients with glomerular ***,although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases,clinical trials reported contrasting ***,at this moment,there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary ***,we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.

关键词： Costimulation Glomerulonephritis Cluster of differentiation 80 Cytotoxic T-lymphocyte-associated antigen-4 Lupus nephritis Abatacept Proteinuria Podocytes

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Present and future of immune checkpoint blockade: Monotherapy to adjuvant approaches

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World Journal of Immunology 2015年第1期5卷 1-15页

作者： Mira A Patel Jennifer E Kim Jacob Ruzevick Michael Lim Department of Neurosurgery the Johns Hopkins University School of Medicine Department of Oncology the Johns Hopkins University School of Medicine

Immune regulation of aggressive tumor growth is often outpaced by tumor up-regulation of ligands that inhibit effector immune responses through the activation of immune checkpoints. A few of such checkpoints include programmed death-1(PD-1), cytotoxic T lymphocyte associated antigen-4(CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin and mucin protein-3, Glucocorticoid-induced TNFR family-related receptor(GITR), and killer cell immunoglobulin like receptor. With the exception of GITR, after binding to their respective ligands these checkpoints induce down-modulation of immune responses to prevent autoimmunity. However, such immune mechanisms are co-opted by tumors to allow rapid tumor cell proliferation. Pre-clinical studies in antibody blockade of PD-1 and CTLA-4 have led to promising augmentation of effector immune responses in murine tumor models, and human antibodies against PD-1 and CTLA-4 alone or in combination have demonstrated tumor regression in clinical trials. The development of immune checkpoint blockade as a potential future immunotherapy has led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemotherapy and radiation therapy has shown synergistic effects in pre-clinical and clinical studies, and combination checkpoint blockade with bacterial vaccine vectors have produced increased effector immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.

关键词： Programmed death-1 Cytotoxic T lymphocyte associated antigen-4 Ipilimumab Nivolumab Immune checkpoint

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