Journal Articles

Immunotherapy reviews

Reviews on preclinical or clinical cancer immunotherapy approaches

Fusogenic Viruses in Oncolytic Immunotherapy

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Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune responses directed against the tumor, make oncolytic viruses highly attractive candidates for immunotherapy. Increasing evidence indicates that a subclass of oncolytic viruses, which encodes for fusion proteins, could outperform non-fusogenic viruses, both in their direct oncolytic potential, as well as their immune-stimulatory properties. Tumor cell infection with these viruses leads to characteristic syncytia formation and cell death due to fusion, as infected cells become fused with neighboring cells, which promotes intratumoral spread of the infection and releases additional immunogenic signals. In this review, we discuss the potential of fusogenic oncolytic viruses as optimal candidates to enhance immunotherapy and initiate broad antitumor responses. We provide an overview of the cytopathic mechanism of syncytia formation through viral-mediated expression of fusion proteins, either endogenous or engineered, and their benefits for cancer therapy. Growing evidence indicates that fusogenicity could be an important feature to consider in the design of optimal oncolytic virus platforms for combinatorial oncolytic immunotherapy.

Author Info: (1) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. teresa.krabbe@tum.de. (2) 2nd Department of Internal Medicine, Klinikum

Author Info: (1) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. teresa.krabbe@tum.de. (2) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. jennifer.altomonte@tum.de.

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PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy

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Cancer immunotherapy has greatly advanced in recent years, and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy. Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients, which promoted the Food and Drug Administration (FDA) approval of PD-1/PD-L1 blocking drugs. In this review, we provide a detailed introduction of five PD-1/PD-L1 blocking drugs, with indications and studies, as a valuable reference for doctors and medical investigators. Moreover, the characteristics of PD-1/PD-L1 blocking therapies, including their universality and sustainability, are discussed in this review. Furthermore, we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment, and the current status of combination therapies.

Author Info: (1) Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational

Author Info: (1) Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational Ministry, Tianjin Medical University, Tianjin 300070, China. (2) Institute of Integrative Medicines for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin 300100, China. (3) Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational Ministry, Tianjin Medical University, Tianjin 300070, China. Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.

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Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients

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Immune checkpoint inhibitors (ICIs) have revolutionized treatment landscape among non-small cell lung cancer (NSCLC) patients in first- and second-line setting, and may become soon new treatment options in other thoracic malignancies such as small cell lung cancer (SCLC) or mesothelioma. The use of these drugs has indubitably changed the toxicity profile the oncologists are familiar with, and new spectra of immune-related adverse events are being reported with the widespread use of immunotherapies in solid tumors. Clinical management and understanding of immune-related adverse events is new and complex but expertise is still limited. In this review, we are summarizing the incidence and management of main side effects related to ICIs focusing on NSCLC patients.

Author Info: (1) Medical Oncology Department, Hospital Vall d'Hebron, Passeig de la Vall d'Hebron, Barcelona, Spain. (2) Gustave Roussy, Departement de Medecine Oncologique, Universite Paris-Saclay, Villejuif, France

Author Info: (1) Medical Oncology Department, Hospital Vall d'Hebron, Passeig de la Vall d'Hebron, Barcelona, Spain. (2) Gustave Roussy, Departement de Medecine Oncologique, Universite Paris-Saclay, Villejuif, France. (3) Oncoavanze-Quiron Sevilla, Sevilla, Spain. (4) Medical Oncology Department, Hospital Clinic Barcelona, Villarroel, Barcelona, Spain. (5) Medical Oncology Department, Hospital Clinic Barcelona, Villarroel, Barcelona, Spain.

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Strategies to enhance NK cell function for the treatment of tumors and infections

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Natural killer (NK) cells are innate immune cells equipped with the ability to rapidly kill stressed cells that are neoplastic or virally infected. These cells are especially important in settings where these stressed cells downregulate MHC class I molecules and evade recognition by cytotoxic T cells. However, the activity of NK cells alone is often suboptimal to fully control tumor growth or to clear viral infections. Thus, the enhancement of NK cell function is necessary to fully harness their antitumor or antiviral potential. In this review, we discuss how NK cell function can be augmented by the modulation of signal transduction pathways, by the manipulation of inhibitory/activating receptors on NK cells, and by cytokine-induced activation. We also discuss how some of these strategies are currently impacting NK cells in the treatment of cancer and infections.

Author Info: (1) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (2) Department of Pathology and Laboratory Medicine, Perelman

Author Info: (1) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (2) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (3) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Targeting the Immune Microenvironment in Acute Myeloid Leukemia: A Focus on T Cell Immunity

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Immunotherapies, such as chimeric antigen receptor T cells, bispecific antibodies, and immune checkpoint inhibitors, have emerged as promising modalities in multiple hematologic malignancies. Despite the excitement surrounding immunotherapy, it is currently not possible to predict which patients will respond. Within solid tumors, the status of the immune microenvironment provides valuable insight regarding potential responses to immune therapies. Much less is known about the immune microenvironment within hematologic malignancies but the characteristics of this environment are likely to serve a similar predictive role. Acute myeloid leukemia (AML) is the most common hematologic malignancy in adults, and only 25% of patients are alive 5 years following their diagnosis. There is evidence that manipulation of the immune microenvironment by leukemia cells may play a role in promoting therapy resistance and disease relapse. In addition, it has long been documented that through modulation of the immune system following allogeneic bone marrow transplant, AML can be cured, even in patients with the highest risk disease. These concepts, along with the poor prognosis associated with this disease, have encouraged many groups to start exploring the utility of novel immune therapies in AML. While the implementation of these therapies into clinical trials for AML has been supported by preclinical rationale, many questions still exist surrounding their efficacy, tolerability, and the overall optimal approach. In this review, we discuss what is known about the immune microenvironment within AML with a specific focus on T cells and checkpoints, along with their implications for immune therapies.

Author Info: (1) Pediatric Hematology/Oncology, Seattle Children's Hospital, Seattle, WA, United States. (2) Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States.

Author Info: (1) Pediatric Hematology/Oncology, Seattle Children's Hospital, Seattle, WA, United States. (2) Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States.

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Tumor microenvironment: recent advances in various cancer treatments

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This is a review regarding different types of cancer treatments. We aimed at analyzing the tumor microenvironment and the recent trends for the therapeutic applications and effectiveness for several kinds of cancers. Traditionally the cancer treatment was based on the neoplastic cells. Methods such as surgery, radiation, chemotherapy, and immunotherapy, which were targeted on the highly proliferating mutated tumor cells, have been investigated. The tumor microenvironment describes the non-cancerous cells in the tumor and has enabled to investigate the behavior and response of the cancer cells to a treatment process; it consists in a tissue that may have a predictive significance for tumor behavior and response to therapy. These include fibroblasts, immune cells and cells that comprise the blood vessels. It also includes the proteins produced by all of the cells present in the tumor that support the growth of the cancer cells. By monitoring changes in the tumor microenvironment using its molecular and cellular profiles as the tumor progresses will be vital for identifying cell or protein targets for the cancer prevention and its therapeutic purposes.

Author Info: (1) Department of General Surgery, Chun'an First People's Hospital, (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China. 25852832@qq.com. (2) (3)

Author Info: (1) Department of General Surgery, Chun'an First People's Hospital, (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China. 25852832@qq.com. (2) (3)

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Human adaptive immune receptor repertoire analysis-Past, present, and future

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The genes encoding adaptive immune antigen receptors, namely the immunoglobulins expressed in membrane-bound or secreted forms by B cells, and the cell surface T cell receptors, are unique in human biology because they are generated by combinatorial rearrangement of the genomic DNA. The diversity of receptors so generated in populations of lymphocytes enables the human immune system to recognize antigens expressed by pathogens, but also underlies the pathological specificity of autoimmune diseases and the mistargeted immunity in allergies. Several recent technological developments, foremost among them the invention of high-throughput DNA sequencing instruments, have enabled much deeper and thorough evaluation of clones of human B cells and T cells and the antigen receptors they express during physiological and pathogenic immune responses. The evolutionary struggles between host adaptive immune responses and populations of pathogens are now open to greater scrutiny, elucidation of the underlying reasons for successful or failed immunity, and potential predictive modeling, than ever before. Here we give an overview of the foundations, recent progress, and future prospects in this dynamic area of research.

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. (2) Department of Pathology, Stanford University, Stanford, CA, USA.

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. (2) Department of Pathology, Stanford University, Stanford, CA, USA.

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Assessing human B cell repertoire diversity and convergence

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A hallmark of the adaptive immune system is the specificity of B cell and T cell responses. Mechanistically, this feature relies on the fact that the two genes that encode B cell and T cell antigen receptors are not germline encoded and instead are assembled from a large number of small gene segments during lymphocyte development. The underlying somatic gene recombination process can generate a quasi-unlimited repertoire of antigen receptors. The high degree of diversity is essential to guarantee recognition of nearly any antigenic structure to protect from the large variety of potential invading pathogens and to keep the balance with commensals. Due to the enormous complexity of the antigen receptor repertoire, our understanding of its actual size and functional convergence at the level of the individual and the population is still limited. A better understanding of the actual degree of diversity could help to predict adaptive immune responses and would have wide implications for the development of preventive and therapeutic measures against infectious and autoimmune diseases as well as cancer. Here, we discuss the recent advances in the field with a specific focus on B cells and the function of antibodies.

Author Info: (1) German Cancer Research Center, B Cell Immunology, Heidelberg, Germany. (2) German Cancer Research Center, B Cell Immunology, Heidelberg, Germany.

Author Info: (1) German Cancer Research Center, B Cell Immunology, Heidelberg, Germany. (2) German Cancer Research Center, B Cell Immunology, Heidelberg, Germany.

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Bohemian T cell receptors: sketching the repertoires of unconventional lymphocytes

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Over the last several decades, novel populations of unconventional T cells have been identified; defined by an invariant (or nearly invariant) T cell receptor (TCR) with a fixed specificity to non-canonical antigens and major histocompatibility (MHC) molecules, they form large, functionally monoclonal populations tasked with surveying for their specific antigens. With residence in both lymphoid and non-lymphoid tissues coupled with their ability to rapidly produce a spectrum of cytokines and effector molecules, the unconventional T cells are poised as some of the first responders to infection/damage and are thought to provide critical coverage before more focused, conventional T cell responses are mobilized. However, new technologies for the measurement and characterization of TCR repertoires have identified an underappreciated amount of TCR diversity in the unconventional T cells. In many cases, the specificities of these diverse TCRs converge on the same or similar antigens as their invariant counterparts, while others have yet to be defined. Here, we will review the current knowledge of the TCR repertoires of unconventional T cells and discuss how repertoires might be used as a framework for their organization, and further our understanding of their role not only during an immune response, but also their contribution in maintaining homeostasis.

Author Info: (1) St. Jude Children's Research Hospital, Memphis, TN, USA. (2) St. Jude Children's Research Hospital, Memphis, TN, USA.

Author Info: (1) St. Jude Children's Research Hospital, Memphis, TN, USA. (2) St. Jude Children's Research Hospital, Memphis, TN, USA.

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Clinical efficacy and safety of CIK plus radiotherapy for lung cancer: A meta-analysis of 16 randomized controlled trials

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OBJECTIVE: Cytokine-induced killer cells (CIK) therapy is the most commonly used cellular immunotherapy. The CIK plus radiotherapy was clinically used in a wide range of treatment, but the efficacy of their combination against lung cancer is not clear yet. Therefore, we systematically evaluated all the related studies to reveal the combination's clinical efficacy and safety in lung cancer. MATERIALS AND METHODS: We collected all the studies about CIK plus radiotherapy for lung cancer in Medline, Embase, Web of Science (ISI), China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journals Full-Text Database (VIP), Wanfang Database, China Biological Medicine Database (CBM) and Cochrane Central Register of Controlled Trials (CENTRAL), Chinese clinical trial registry (Chi-CTR), WHO International Clinical Trials Registry Platform (WHO-ICTRP) and US-clinical trials (March 2017). We evaluated their bias risk according to the Cochrane evaluation handbook of randomized controlled trials (RCTs), extracted all the data, and synthesized the data using meta analysis. RESULTS: We included 16 RCTs involving 1197 patients with lung cancer, and most trials had unclear risk of bias. Meta-analysis showed that CIK therapy could increase the objective response rate (ORR) (1.32, 1.21 to 1.44), the disease control rate (DCR) (1.13, 1.04 to 1.23), the 1-year overall survival (OS) rate (1.38, 1.16 to 1.63) and the 2-year OS rate (1.23, 1.11 to 1.35). DCs-CIK cells increased the 3-year OS rate (1.66, 1.20 to 2.29). DCs-CIK therapy could increase the CD3(+)T cells (2.27, 1.47 to 3.06), CD4(+)T cells (1.28, 0.74 to 1.81), NK cells (2.04, 0.74 to 3.33) and CD4(+)/CD8(+) T cells ratio (1.20, 0.64 to 1.76) and decrease the CD8(+)T cells (-0.84, -1.60 to -0.08). CIK plus radiotherapy had lower risk of leukopenia (0.85, 0.76 to 0.95) and higher risk of fever (5.50, 2.71 to 11.17) than that of radiotherapy alone. Subgroup analysis showed that CIK plus radiotherapy, mainly three dimensional conformal radiotherapy (3D-CRT) could increase the ORR, DCR, 1- and 2- year OS rate in non-small cell lung cancer (NSCLC), and only DCR in small cell lung cancer (SCLC). Compared with CIK plus pure radiotherapy, except for the ORR, DCR, 1-year OS rate, CIK plus chemoradiotherapy could still increase the 2-year OS rate. DCs-CIK could increase the ORR, DCR, 1- and 2-year OS rate, CIK cells could only increase the ORR and the 1-year OS rate. CONCLUSIONS: CIK plus radiotherapy can improve the clinical response, OS and PFS in lung cancer. It may have low risk of leukopenia and high risk of fever. CIK plus chemoradiotherapy, mainly 3D-CRT can improve the clinical response, OS and PFS in NSCLC. DCs-CIK cells can improve the 1-, 2- and 3-year OS rate, and the 1- and 2-year PFS rate, and CIK cells only improve the 1-year OS rate. DCs-CIK cells can repair the antitumor immunity.

Author Info: (1) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China

Author Info: (1) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. Electronic address: zy426f@163.com. (2) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (3) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (4) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (5) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (6) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (7) Department of Immunology, Southwest Medical University, Luzhou 646000, Sichuan, China. (8) Department of Oncology, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. Electronic address: fengjh100@163.com. (9) Department of Immunology, Zunyi Medical College, Zunyi 563000, Guizhou, China. (10) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Respiratory Medicine (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (11) Evidence-Based Medicine Center of Lanzhou University, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu, China. (12) Evidence-Based Medicine Center, MOE Virtual Research Center of Evidence-based Medicine at Zunyi Medical College, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China; Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China. (13) Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China. (14) Department of Immunology, Southwest Medical University, Luzhou 646000, Sichuan, China. (15) Outpatient Department of Psychological Counseling Clinic (Center for Evidence-Based and Translational Medicine of major infectious diseases), Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou, China.

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