Journal Articles

Immunotherapy reviews

Reviews on preclinical or clinical cancer immunotherapy approaches

Transcriptional retargeting of herpes simplex virus for cell-specific replication to control cancer

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INTRODUCTION: Oncolytic virotherapy has emerged as a novel frontier in the treatment of cancer. Among the viruses that entered clinical trials are the oncolytic herpes simplex virus-1 (HSV-1). Current oncolytic HSV-1 approved for clinical practice, and those in clinical trials are attenuated viruses, often deleted in the neurovirulence gene gamma134.5, and in additional genes, which may result in a much more attenuated virus with reduced replication efficiency. Therefore, the transcriptional retargeting strategy by modifying the regulator elements flanking essential viral genes to achieve tumor-specific replication while maintaining as much of the viral genome has been representing alternative promising oncolytic virotherapy modality. MATERIALS AND METHODS: In this communication, we aimed to review extensive studies on transcriptional retargeting strategy with HSV-1 genome engineered on immediate-early ICP4 gene, late gamma134.5 gene or early ICP6 gene as well as multiple-regulated oncolytic HSV1 through combining transcriptional retargeting and translational control. Design modality based on differential cellular background, advantage, and potential clinic limitation of the innovative oncolytic HSV-1 was described, and prospective and challenge of transcriptional retargeting strategy were collectively summarized. CONCLUSION: Transcriptional retargeting strategy holds great promise in retaining tumor specificity as well as full replication capacity of oncolytic virus in the target cell as urgently required by clinical trials. Future efforts should be aimed toward the development of multiple-component targeted oncolytic virus such as combing the transcriptional retargeting strategy and genetically attenuated modulation or post-transcriptional control that will be the most effective at generating truly tumor selective vectors.

Author Info: (1) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology

Author Info: (1) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. (2) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. (3) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. (4) Viri Biotechnology Company Limited, No. 8 Guohuai Street, Zhengzhou, Henan, 450052, China. (5) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. diwen163@163.com. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. diwen163@163.com. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. diwen163@163.com. Viri Biotechnology Company Limited, No. 8 Guohuai Street, Zhengzhou, Henan, 450052, China. diwen163@163.com. (6) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. ningning1723@126.com. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. ningning1723@126.com.

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Modulating Tumor Immunology by Inhibiting Indoleamine 2,3-Dioxygenase (IDO): Recent Developments and First Clinical Experiences

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the first rate-limiting step in the oxidative metabolism of compounds containing indole rings, including the transformation of the essential amino acid L-tryptophan to N-formyl-L-kynurenine. Through direct and indirect means, IDO exerts both tolerogenic and pro-inflammatory effects and has a profound immunoregulatory role in the tumor microenvironment. Although the role of IDO in mediating peripheral acquired immunologic tolerance has been known for some time, its role in tumorigenesis and the subversion of anti-tumor immunity have only recently been appreciated. Small-molecule inhibitors of IDO1 and TDO are being evaluated as single agents and in combination with immune checkpoint blockade in a host of advanced cancers. In this review, we delineate the tolerogenic and pro-inflammatory effects of IDO as it relates to immune escape and discuss current clinical progress in this area.

Author Info: (1) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. (2) Department of Medicine, Division of

Author Info: (1) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. (2) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. baharyn@upmc.edu.

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Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles

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Lung cancer is one of the leading causes of death worldwide. There are 2 major subtypes of lung cancer, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Studies show that NSCLC is the more prevalent type of lung cancer that accounts for approximately 80%-85% of cases. Although, various treatment methods, such as chemotherapy, surgery, and radiation therapy have been used to treat lung cancer patients, there is an emergent need to develop more effective approaches to deal with advanced stages of tumors. Recently, immunotherapy has emerged as a new approach to combat with such tumors. The development and success of programmed cell death 1 (PD-1)/program death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockades in treating metastatic cancers opens a new pavement for the future research. The current mini review discusses the significance of immune checkpoint inhibitors in promoting the death of tumor cells. Additionally, this review also addresses the importance of tumor-specific antigens (neoantigens) in the development of cancer vaccines and major challenges associated with this therapy. Immunotherapy can be a promising approach to treat NSCLC because it stimulates host's own immune system to recognize cancer cells. Therefore, future research should focus on the development of new methodologies to identify novel checkpoint inhibitors and potential neoantigens.

Author Info: (1) Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

Author Info: (1) Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

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Pembrolizumab in advanced pretreated small cell lung cancer patients with PD-L1 expression: data from the KEYNOTE-028 trial: a reason for hope

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Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer, representing around 15% of all lung cancer cases. SCLC is characterized by neuroendocrine pathological features, strong association with tobacco exposure, rapid widespread, high mutational rates and no oncogenic drivers (1). At diagnosis, around 70% of cases present with extensive disease (ED-SCLC). Platinum-etoposide doublet is the standard of care, offering response rates of 70_80%. However, despite this initial significant chemosensitivity, progression of the disease will occur after completion of chemotherapy, with median progression-free survival (PFS) of only 2_3 months. In the refractory setting, topotecan offers modest benefit, with response rates of 10% to 20%, and significant toxicity. Consequently, the overall prognosis for patients with ED-SCLC is poor, with median overall survival (OS) of 8_13 months and 5-year OS rate of 1_2% (2)

Author Info: (1) Medical Oncology Department, Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (2) Medical Oncology Department, Vall d'Hebron Hospital and Vall

Author Info: (1) Medical Oncology Department, Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (2) Medical Oncology Department, Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

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The reproducibility of PD-L1 scoring in lung cancer: can the pathologists do better

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In the era of personalized medicine, the selection of advanced stages non-small cell lung cancer (NSCLC) patients for targeted treatments requires development, validation and continuous quality assessments of a wide array of laboratory assays, including both conventional and developing methodologies. While high throughput molecular testing approaches, to extensively assess genomic biomarkers of current and potential clinical value, are fascinating innovations in the field of modern oncology, traditional morpho-molecular methodologies such as fluorescent in situ hybridisation and immunohistochemical (IHC) techniques are still precious in the clinic to guide therapeutic interventions (1). This holds even more true, when considering the recent requirements to evaluate in NSCLC cells the checkpoint inhibitor programmed cell death ligand 1 (PD-L1) protein expression. Different primary antibody clones, raised against different epitopes (parts) of the PD-L1, are available (2). Each clone is linked to a specific treatment: clone 28-8 (Dako, Glostrup, Denmark) for nivolumab, 22C3 (Dako) for pembrolizumab, SP142 (Ventana, Tucson, AZ, USA) for atezolizumab and SP263 (Ventana) for durvalumab. Different clinical trial performed its own PD-L1 immunohistochemistry assay as a prepackaged kit of reagents running on company-specific staining platforms according to the manufacturersinstructions either on the Dako Link AS-48 (no longer available commercially) or on the Ventana Benchmark autostainer systems, adopting custom scoring-criteria for each assay (2)

Author Info: (1) Department of Public Health, University of Naples Federico II, Naples, Italy. (2) Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy.

Author Info: (1) Department of Public Health, University of Naples Federico II, Naples, Italy. (2) Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy.

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Small-cell lung cancer in the era of immunotherapy

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Small-cell lung cancer represents about 13_15% of all lung cancers, accounting for more than 275,000 new cases worldwide every year (1). It is a poorly differentiated, high-grade carcinoma thought to originate from neuroendocrine-cell precursors within the bronchi. Small-cell lung cancer is strongly associated with heavy tobacco exposure and typically has a high mutation burden. To date, no targeted therapy has been proven to be effective in small cell lung cancer patients (1,2). Small-cell lung cancer has a high incidence of early metastasis. At diagnosis, about 70% of patients have extensive-stage disease, defined as the presence of metastatic disease by imaging or physical examination outside the hemithorax; the remaining 30% of patients have limited-stage disease, in which tumor involvement is confined to one hemithorax and can be treated in a tolerable radiation field.

Author Info: (1) Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. (2) Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New

Author Info: (1) Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. (2) Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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Reproducibility of PD-L1 assessment in non-small cell lung cancer-know your limits but never stop trying to exceed them

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Immunotherapy targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has demonstrated strong and durable anti-tumoral immune responses with significantly improved overall survival in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) (1). PD-1 or CD279 is a type 1 transmembrane protein expressed on the surface of activated immune cells, including T cells, B cells, monocytes, natural killer cells, regulatory T cells, dendritic cells, and macrophages (2). The binding of PD-1 to its major ligand PD-L1, B7-H1 or CD274 decreases the ability of activated T cells to produce an effective immune response and prevents the host immune system from destroying tumor cells. PD-L1 is widely expressed in hematopoietic cells, including macrophages, dendritic cells, mast cells, T cells, and B cells, as well as in non-hematopoietic cells, including epithelial, endothelial, and tumor cells (2).

Author Info: (1) Universite Cote d'Azur, University Hospital Federation OncoAge, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. Universite Cote d'Azur, Institute for Research on

Author Info: (1) Universite Cote d'Azur, University Hospital Federation OncoAge, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. Universite Cote d'Azur, Institute for Research on Cancer and Ageing, Nice (IRCAN), Inserm U1081 and UMR CNRS 7284, Nice, France. Universite Cote d'Azur, University Hospital Federation OncoAge, Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France. (2) Universite Cote d'Azur, University Hospital Federation OncoAge, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. Universite Cote d'Azur, Institute for Research on Cancer and Ageing, Nice (IRCAN), Inserm U1081 and UMR CNRS 7284, Nice, France. Universite Cote d'Azur, University Hospital Federation OncoAge, Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France.

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Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade

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Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-gamma signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade. In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy. Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.

Author Info: (1) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (2) Department of Molecular Biology and Bio-Therapeutic

Author Info: (1) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (2) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (3) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (4) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (5) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China. (6) Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China.

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Antibody based EpCAM targeted Therapy of Cancer, Review and update

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Todays, after four decades of the discovery of monoclonal antibodies by Kohler and Milstein in 1975, a dozen of antibodies are used in cancer targeted therapy with different strategies. The success of these antibodies depends on the specificity of antigens expressed on the cancer cells. Epithelial cell adhesion molecule (EpCAM), a homophilic cell-cell adhesion glycoprotein is a well- known tumor antigen, which expresses on epithelial tumors and circulating tumor cells as well as cancer stem cells. The EpCAM signaling pathway is associated with proliferation, differentiation and adhesion of epithelial cancer cells. Here we review EpCAM structure, expression profile and its signaling pathway in cancer cells. In addition, we focused on structure, mechanism of action and success of anti EpCAM antibodies which have been used in different clinical trials. Based on literatures, Edrecolomab show limited efficacy in the phase III studies. The wholly monoclonal antibody Adecatumumab is dose- and target-dependent in metastatic breast cancer patients expressing EpCAM. The chimeric antibody Catumaxomab is approved for the treatment of malignant ascites; however, this Mab showed considerable results in intrapleural administration in cancer patients. Anti EpCAM toxin conjugated antibodies Oportuzumab Monatox (scFv antibody and Pseudomonas exotoxin A (ETA)) and Citatuzumab Bogatox (Fab fragment with bouganin toxin) and also, immono-conjugate antibody Tucotuzumab (wholly monoclonal antibody with IL2), shown acceptable results in different clinical trials. Almost, all of the antibodies were well- tolerated; however, still more clinical trials are needed for approval of the antibodies for treatment of specific tumors.

Author Info: (1) Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran. (2) Biotechnology Research Center, Tabriz University of

Author Info: (1) Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran. (2) Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz. Iran. (3) Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz. Iran. (4) Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz. Iran. (5) Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science. Tabriz. Iran. (6) Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran.

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KEYNOTE-028: how do we use immunotherapy in small cell lung cancer

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Recently, PD-1 axis inhibition has started to show activity in small cell lung cancer (SCLC), enough to suggest that, at last, a new treatment option for SCLC may have arrived. Nivolumab and nivolumab + ipilimumab are now both listed in the NCCN guidelines for second line or beyond therapy in SCLC, based on data from the Checkmate-032 study, although neither of these regimens has yet been approved by the FDA (1). Additionally, a small phase Ib study (KEYNOTE-028) recently published inhe Journal of Clinical Oncologyy Ottt al.as explored the use of pembrolizumab monotherapy in previously treated extensive stage SCLC (2). The emergence of immunotherapy as a therapeutic option in SCLC is exciting, but there is still a lot to learn about its true potential in this disease.

Author Info: (1) Thoracic Oncology Program, University of Colorado Cancer Center, Aurora, Colorado, USA. (2) Thoracic Oncology Program, University of Colorado Cancer Center, Aurora, Colorado, USA.

Author Info: (1) Thoracic Oncology Program, University of Colorado Cancer Center, Aurora, Colorado, USA. (2) Thoracic Oncology Program, University of Colorado Cancer Center, Aurora, Colorado, USA.

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