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1
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Pratticò F, Garajová I. Focus on Pancreatic Cancer Microenvironment. Curr Oncol 2024; 31:4241-4260. [PMID: 39195299 PMCID: PMC11352508 DOI: 10.3390/curroncol31080316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.
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Affiliation(s)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy;
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2
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Hidig SM. An Overview of Pancreatic Cancer Diagnosis and Treatment in China: Current Landscape and Future Prospects. Niger Med J 2024; 65:387-397. [PMID: 39398405 PMCID: PMC11470284 DOI: 10.60787/nmj-v65i3-376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024] Open
Abstract
This comprehensive literature review is to summarize the most recent findings regarding the causes, diagnosis, and treatments of pancreatic cancer and to encourage additional investigation into this under-researched malignant tumor. Pancreatic cancer is a significant public health issue in China, with annual mortality rates almost equal to incidence rates. The disease is more prevalent in rural areas and has a poor prognosis. The data was collected from the following databases: Pub Med, Cross ref, Science Direct, Scopus, and Google Scholar we reviewed published articles from 2018 to 2023 on the annual incidence of pancreatic cancer in China is 5.1%, with only 5-7% of patients completely cured. The prognosis is extremely poor, with a 1-year survival rate of 8% and a 5-year survival rate of 3%. Pancreatic cancer has no specific clinical manifestations or tumor markers, and its characteristics are not typical of high-risk factors including smoking, alcohol, chronic pancreatitis, abnormal microorganism metabolism, blood type, and glucose and lipid levels. For increased detection and survival rates, pancreatic cancer must be diagnosed as early as possible. However, the low specificity of tumor markers calls for more study. Future treatment strategies could include immunotherapy and a microbiology-free system, and it's anticipated that they'll offer intriguing clinical applications for extending patients' lives with pancreatic cancer. Finally, we suggest measures to improve the health outcomes of pancreatic cancer patients in China.
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Affiliation(s)
- Sakarie Mustafe Hidig
- Department of Hepatobiliary and Pancreatic Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang Province, 322000, PR. China
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Nikolouzakis TK, Chrysos E, Docea AO, Fragkiadaki P, Souglakos J, Tsiaoussis J, Tsatsakis A. Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy. Cancers (Basel) 2024; 16:1995. [PMID: 38893120 PMCID: PMC11171065 DOI: 10.3390/cancers16111995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other's efficacy, paving the way for promising future therapeutic advancements.
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Affiliation(s)
| | - Emmanuel Chrysos
- Department of General Surgery, University General Hospital of Heraklion, 71110 Heraklion, Greece; (T.K.N.); (E.C.)
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Persefoni Fragkiadaki
- Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece; (P.F.); (A.T.)
| | - John Souglakos
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece;
| | - John Tsiaoussis
- Department of Anatomy, Medical School, University of Crete, 70013 Heraklion, Greece;
| | - Aristidis Tsatsakis
- Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece; (P.F.); (A.T.)
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Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy? Cancers (Basel) 2023; 15:cancers15041116. [PMID: 36831465 PMCID: PMC9953994 DOI: 10.3390/cancers15041116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/24/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here.
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Huang X, Zhang G, Tang TY, Gao X, Liang TB. Personalized pancreatic cancer therapy: from the perspective of mRNA vaccine. Mil Med Res 2022; 9:53. [PMID: 36224645 PMCID: PMC9556149 DOI: 10.1186/s40779-022-00416-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity, especially in genetic alteration and microenvironment. Conventional therapeutic strategies for pancreatic cancer usually suffer resistance, highlighting the necessity for personalized precise treatment. Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting, minimal nonspecific effects, broad therapeutic window, low toxicity, and induction of persistent immunological memory. Multiple conventional vaccines based on the cells, microorganisms, exosomes, proteins, peptides, or DNA against pancreatic cancer have been developed; however, their overall efficacy remains unsatisfactory. Compared with these vaccine modalities, messager RNA (mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment, and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer. This review summarizes the current progress on pancreatic cancer vaccines, highlights the superiority of mRNA vaccines over other conventional vaccines, and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.
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Affiliation(s)
- Xing Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Gang Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Tian-Yu Tang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Xiang Gao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
| | - Ting-Bo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009 China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003 China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003 China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009 China
- Cancer Center, Zhejiang University, Hangzhou, 310058 China
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6
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Zhang J, Li R, Huang S. The immunoregulation effect of tumor microenvironment in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:951019. [PMID: 35965504 PMCID: PMC9365986 DOI: 10.3389/fonc.2022.951019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer has the seventh highest death rate of all cancers. The absence of any serious symptoms, coupled with a lack of early prognostic and diagnostic markers, makes the disease untreatable in most cases. This leads to a delay in diagnosis and the disease progresses so there is no cure. Only about 20% of cases are diagnosed early. Surgical removal is the preferred treatment for cancer, but chemotherapy is standard for advanced cancer, although patients can eventually develop drug resistance and serious side effects. Chemoresistance is multifactorial because of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment (TME). Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. This review focuses on the immune-related components of TME and the interactions between tumor cells and TME during the development and progression of pancreatic cancer, including immunosuppression, tumor dormancy and escape. Finally, we discussed a variety of immune components-oriented immunotargeting drugs in TME from a clinical perspective.
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Affiliation(s)
| | - Renfeng Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuai Huang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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7
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Smith C, Zheng W, Dong J, Wang Y, Lai J, Liu X, Yin F. Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy. World J Gastroenterol 2022; 28:3297-3313. [PMID: 36158269 PMCID: PMC9346457 DOI: 10.3748/wjg.v28.i27.3297] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/22/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.
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Affiliation(s)
- Caitlyn Smith
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Wei Zheng
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Jixin Dong
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Yaohong Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Jinping Lai
- Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, United States
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
| | - Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212, United States
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Nel AE, Mei KC, Liao YP, Lu X. Multifunctional Lipid Bilayer Nanocarriers for Cancer Immunotherapy in Heterogeneous Tumor Microenvironments, Combining Immunogenic Cell Death Stimuli with Immune Modulatory Drugs. ACS NANO 2022; 16:5184-5232. [PMID: 35348320 PMCID: PMC9519818 DOI: 10.1021/acsnano.2c01252] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
In addition to the contribution of cancer cells, the solid tumor microenvironment (TME) has a critical role in determining tumor expansion, antitumor immunity, and the response to immunotherapy. Understanding the details of the complex interplay between cancer cells and components of the TME provides an unprecedented opportunity to explore combination therapy for intervening in the immune landscape to improve immunotherapy outcome. One approach is the introduction of multifunctional nanocarriers, capable of delivering drug combinations that provide immunogenic stimuli for improvement of tumor antigen presentation, contemporaneous with the delivery of coformulated drug or synthetic molecules that provide immune danger signals or interfere in immune-escape, immune-suppressive, and T-cell exclusion pathways. This forward-looking review will discuss the use of lipid-bilayer-encapsulated liposomes and mesoporous silica nanoparticles for combination immunotherapy of the heterogeneous immune landscapes in pancreatic ductal adenocarcinoma and triple-negative breast cancer. We describe how the combination of remote drug loading and lipid bilayer encapsulation is used for the synthesis of synergistic drug combinations that induce immunogenic cell death, interfere in the PD-1/PD-L1 axis, inhibit the indoleamine-pyrrole 2,3-dioxygenase (IDO-1) immune metabolic pathway, restore spatial access to activated T-cells to the cancer site, or reduce the impact of immunosuppressive stromal components. We show how an integration of current knowledge and future discovery can be used for a rational approach to nanoenabled cancer immunotherapy.
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Affiliation(s)
- André E. Nel
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, United States
| | - Kuo-Ching Mei
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Yu-Pei Liao
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Xiangsheng Lu
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer and a leading cause of cancer deaths worldwide. Over 90% of patients die within 1 year of diagnosis. Deaths from PDAC are increasing and it remains a cancer of substantial unmet need. A number of factors contribute to its poor prognosis: namely, late presentation, early metastases and limited systemic therapy options because of chemoresistance. A variety of research approaches underway are aimed at improving patient survival. Here, we review high-risk groups and efforts for early detection. We examine recent developments in the understanding of complex molecular and metabolic alterations which accompany PDAC. We explore artificial intelligence and biological targets for therapy and examine the role of tumour stroma and the immune microenvironment. We also review recent developments with respect to the PDAC microbiome. It is hoped that current research efforts will translate into earlier diagnosis, improvements in treatment and better outcomes for patients.
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Affiliation(s)
- Martyn C Stott
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Lucy Oldfield
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Jessica Hale
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Eithne Costello
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Christopher M Halloran
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
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He Y, Zhou X, Fan X, Zhang B, Ma L, Wu J, Li X. Disease Burden of Pancreatic Cancer — China, 1990−2019. China CDC Wkly 2022; 4:527-531. [PMID: 35812697 PMCID: PMC9257688 DOI: 10.46234/ccdcw2022.056] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/18/2021] [Indexed: 11/14/2022] Open
Abstract
What is already known about this topic? Pancreatic cancer is one of the most malignant tumors of the digestive tract, and the etiology is not clear. Pancreatic cancer has a poor prognosis and high mortality. What is added by this report? Compared with 1990, the burden of pancreatic cancer in China increased significantly in 2019. In 1990 and 2019, the disease burden indicator of male pancreatic cancer was higher than that of females, and pancreatic cancer became more common as age increased, especially above 50 years old. What are the implications for public health practices? This study mainly provided scientific data and references for the prevention and control of pancreatic cancer in people aged 50 and above.
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Affiliation(s)
- Yuan He
- Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
- National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaolong Zhou
- National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xueqi Fan
- National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Bin Zhang
- National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- Inner Mongolia Medical University, Huhehot, Inner Mongolia Autonomous Region, China
| | - Li Ma
- Office of Epidemiology, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jing Wu
- National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- Jing Wu,
| | - Xudong Li
- Office of Epidemiology, Chinese Center for Disease Control and Prevention, Beijing, China
- Xudong Li,
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Truong LH, Pauklin S. Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches. Cancers (Basel) 2021; 13:5028. [PMID: 34638513 PMCID: PMC8507722 DOI: 10.3390/cancers13195028] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.
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Affiliation(s)
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK;
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12
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Huang Y, Yan X, Ren T, Yi F, Li Q, Zhang C. The safety and efficacy of chemotherapy combined with immunotherapy for pancreatic cancer: A meta-analysis. Medicine (Baltimore) 2021; 100:e26673. [PMID: 34398033 PMCID: PMC8294910 DOI: 10.1097/md.0000000000026673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/17/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Since the combination of chemotherapy and immunotherapy, such as new molecular targeted drugs or vaccines, is controversial in terms of survival advantages compared with chemotherapy therapy alone, we conducted a meta-analysis to compare the efficacy and safety of immunotherapy combined with chemotherapy and chemotherapy alone for advanced pancreatic cancer. METHODS We searched PubMed, Embase, and Cochrane Library from the establishment of the database to November 2020. We included some studies that reported pancreatic cancer patients receiving immunotherapy, and we excluded duplicate publications, research without full text, incomplete information or inability to conduct data extraction, animal experiments, reviews, and systematic reviews. RESULTS The risk ratio of the objective response rate and disease control rate was 1.10 (95% confidence interval [CI]: 0.88-1.38) and 1.17 (95% CI: 1.06-1.31), respectively, indicating that there was no significant difference between the objective response rate of combination therapy and chemotherapy alone, while the disease control rate of the combined treatment was higher than that of chemotherapy alone. The hazard ratio of overall survival and progression-free survival was 0.91 (95% CI: 0.82-1.01) and 0.87 (95% CI: 0.77-0.98), respectively, indicating that there was no significant difference between the overall survival of combination therapy and chemotherapy alone, while progression-free survival of the combined treatment was longer than that of chemotherapy alone. We also found that in addition to the combination treatment, the incidence of vomiting in pancreatic cancer was higher than that of chemotherapy alone, and the incidence of other complications was not significantly different from that of treatment alone. CONCLUSION Chemotherapy combined with immunotherapy for pancreatic cancer not only improves treatment efficiency but also does not cause serious adverse reactions. This treatment strategy should be widely used clinically.
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Zhu L, Lu P, Gong L, Lu C, Li M, Wang Y. Design, Synthesis, and Biological Evaluation of 4-amino Substituted 2Hchromen- 2-one Derivatives as an NEDD8 Activating Enzyme Inhibitor in Pancreatic Cancer Cells. Med Chem 2021; 16:969-983. [PMID: 31880252 DOI: 10.2174/1573406416666191227121520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 12/10/2019] [Accepted: 12/10/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in carcinomas. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment. OBJECTIVE In this article, we decided to study the synthesis and screening of 4-amino substituted 2H-chromen-2-one derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3. METHODS After synthesis of twenty targeted compounds, we evaluated their anti-proliferative activity against six cancer cell lines, cytotoxicity against three normal cell lines through MTT assay, and hemolysis to screen out the candidate compound, which was further conducted drug-like physical property measurement, target confirmation by enzyme-based experiment, cell apoptosis, and synergistic effect research. RESULTS Starting from intermediates 4 and 5, several new 4-amino substituted 2H-chromen-2-one derivatives (9-28) were synthesized and evaluated for their cell activities using six cancer cell lines. We performed tests of cytotoxicity, hemolysis, ATP-dependent NAE inhibition in the enzyme- based system, apoptosis, and synergistic effect in BxPC-3 cells against the best candidate compound 21. CONCLUSION Based on these results, we found that compound 21 inhibited NAE activity in an ATP-dependent manner in the enzyme-based system, induced apoptosis in BxPC-3 cells, and synergized with bortezomib on BxPC-3 cell growth inhibition. Additionally, it had low toxicity with reasonable Log P-value and water solubility.
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Affiliation(s)
- Lijuan Zhu
- School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China
| | - Peng Lu
- School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China
| | - Lei Gong
- School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China
| | - Cheng Lu
- School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China
| | - Mengli Li
- School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China
| | - Yubin Wang
- School of Pharmaceutical Sciences, Nanjing Tech University, No. 5 Xinmofan Road, Nanjing 210009, China
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14
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Kaur J, Mir T, Gill R, Duong J, Marcus S, Khan R. Immunotherapeutic approach for advanced pancreatic adenocarcinoma. Immunotherapy 2021; 13:767-782. [PMID: 33910383 DOI: 10.2217/imt-2020-0344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the USA and the seventh leading cause of cancer-related death worldwide. Most of the patients' presentation is in advanced stages and remains resistant to currently available standard therapies. An in-depth understanding of PDAC's pathogenesis has shown that immunotherapy could bring about a revolution in the treatment response. Immunotherapy in PDAC appears promising in preclinical studies but failed to show benefits in clinical studies. These novel agents' therapeutic failure can be attributed to multiple variables including the tumor microenvironment, early metastasis, tumor heterogeneity and resistance to therapy. There is a need to develop biomarkers for the patient's stratification and provide individualized treatment to improve treatment outcomes.
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Affiliation(s)
- Jasmeet Kaur
- Department of Internal Medicine, Saint Joseph Mercy Oakland Hospital, Pontiac, MI 48341, USA
| | - Tanveer Mir
- Department of Internal Medicine, Wayne State University, Detroit Medical Center, Detroit, MI 48201, USA
| | - Randip Gill
- Department of Internal Medicine, Saint Joseph Mercy Oakland Hospital, Pontiac, MI 48341, USA
| | - Jacky Duong
- Department of Internal Medicine, Saint Joseph Mercy Oakland Hospital, Pontiac, MI 48341, USA
| | - Sapna Marcus
- Department of Radiation Oncology, All India Institute of Medical Sciences & Research, Bathinda, India
| | - Rafiullah Khan
- Department of Internal Medicine, Division of Hematology & Oncology, University of Cincinnati, OH 45267, USA
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15
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Kiaie SH, Sanaei MJ, Heshmati M, Asadzadeh Z, Azimi I, Hadidi S, Jafari R, Baradaran B. Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development. Acta Pharm Sin B 2021; 11:1083-1097. [PMID: 34094821 PMCID: PMC8144893 DOI: 10.1016/j.apsb.2020.12.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/29/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Immunotherapy has been recently considered as a promising alternative for cancer treatment. Indeed, targeting of immune checkpoint (ICP) strategies have shown significant success in human malignancies. However, despite remarkable success of cancer immunotherapy in pancreatic cancer (PCa), many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far. In this process, immunosuppression in the tumor microenvironment (TME) is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method. In this paper, the latest findings on the ICPs, which mediate immunosuppression in the TME have been reviewed. In addition, different approaches for targeting ICPs in the TME of PCa have been discussed. This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.
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Affiliation(s)
- Seyed Hossein Kiaie
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5173957616, Iran
- Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
| | - Mohammad Javad Sanaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8815713471, Iran
| | - Masoud Heshmati
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8815713471, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5173957616, Iran
| | - Iman Azimi
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7001, Tasmania, Australia
| | - Saleh Hadidi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8815713471, Iran
| | - Reza Jafari
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia 5714783734, Iran
- Department of Immunology and Genetics, School of Medicine, Urmia University of Medical Sciences, Urmia 5714783734, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5173957616, Iran
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16
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DeVito NC, Kelleher C, Strickland KC, Abbruzzese J, Anders C, Hanks BA, Jia J, Mettu NB, Morse MA, O’Neill M, Uronis H, Zafar Y, Strickler JH. A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis. AME Case Rep 2021; 5:14. [PMID: 33912803 PMCID: PMC8060150 DOI: 10.21037/acr-20-154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/14/2021] [Indexed: 11/06/2022]
Abstract
Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and HER2 amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, HER2 amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.
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Affiliation(s)
- Nicholas C. DeVito
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - Colm Kelleher
- Department of Radiology, Duke University, Durham, NC, USA
| | | | - James Abbruzzese
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - Carey Anders
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - Brent A. Hanks
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Jingquan Jia
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - Niharika B. Mettu
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - Michael A. Morse
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | | | - Hope Uronis
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - Yousuf Zafar
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
| | - John H. Strickler
- Duke Cancer Institute, Durham, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA
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17
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Principe DR, Korc M, Kamath SD, Munshi HG, Rana A. Trials and tribulations of pancreatic cancer immunotherapy. Cancer Lett 2021; 504:1-14. [PMID: 33549709 DOI: 10.1016/j.canlet.2021.01.031] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 02/09/2023]
Abstract
Immunotherapy has revolutionized cancer treatment in the last decade, and strategies to re-activate cytotoxic immunity are now standard of care in several malignancies. Despite rapid advances in immunotherapy for most solid cancers, progress in immunotherapy against pancreatic ductal adenocarcinoma (PDAC) has been exceptionally difficult. This is true for several approaches, most notably immune checkpoint inhibitors (ICIs) and GM-CSF cell-based vaccines (GVAX). Though many immunotherapies have been explored in clinical trials, few have shown significant therapeutic efficacy. Further, many have shown high rates of serious adverse effects and dose-limiting toxicities, and to date, immunotherapy regimens have not been successfully implemented in PDAC. Here, we provide a comprehensive summary of the key clinical trials exploring immunotherapy in PDAC, followed by a brief discussion of emerging molecular mechanisms that may explain the relative failure of immunotherapy in pancreas cancer thus far.
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Affiliation(s)
- Daniel R Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA; Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.
| | - Murray Korc
- Department of Developmental and Cell Biology, University of California, Irvine, CA, USA
| | - Suneel D Kamath
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
| | - Hidayatullah G Munshi
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
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18
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Chen H, Yang G, Xiao J, Zheng L, You L, Zhang T. Neoantigen-based immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Cancer Lett 2020; 490:12-19. [PMID: 32590021 DOI: 10.1016/j.canlet.2020.06.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/05/2020] [Accepted: 06/12/2020] [Indexed: 02/08/2023]
Abstract
Neoantigens generated in neoplasms are a type of protein completely absent in healthy tissues. Therefore, anti-tumor immunity targeting neoantigens is highly specific, which provides an optional approach to boost tumor immunotherapy. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies in humans, with few efficient treatments to improve its prognosis. Therefore, immunotherapies reinforced by neoantigen-based strategies should be considered. In PDAC, the mutational burden is intermediate compared with other common malignancies, while the naturally formed tumor immunity is significantly inferior. Moreover, the high mutation load in PDAC correlates with a poor clinical prognosis, although the combination of a large mutation repertoire and competent T cell population is indispensable for long-term survival. In clinical practice, three strategies have been mainly used: peptide or tumor cell vaccines, neo-epitope-coding nucleotide vaccines, and dendritic cell vaccines. However, three major problems remain to be addressed, including (1) highly personalized protocols after sampling, (2) insufficient neoantigen quantity, and (3) ineffective immunotherapy of PDAC. In summary, neoantigen-based therapy of PDAC is increasing and the treatment methods are accompanied by great challenges. Currently, extensive development is needed for effective neoantigen-based therapy.
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Affiliation(s)
- Hao Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; School of Medicine, Tsinghua University, 1 Tsinghua Yuan Haidian District, Beijing, 100084, China.
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Jianchun Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China; Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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19
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Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol 2020; 17:527-540. [PMID: 32398706 PMCID: PMC7442729 DOI: 10.1038/s41571-020-0363-5] [Citation(s) in RCA: 727] [Impact Index Per Article: 145.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2020] [Indexed: 12/17/2022]
Abstract
Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Pancreatic Cancer Center for Clinical Research and Care, and The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth M Jaffee
- Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Pancreatic Cancer Center for Clinical Research and Care, and The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Pancreatic Cancer Center for Clinical Research and Care, and The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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20
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Wan Y, Zhang Y, Wang G, Mwangi PM, Cai H, Li R. Recombinant KRAS G12D Protein Vaccines Elicit Significant Anti-Tumor Effects in Mouse CT26 Tumor Models. Front Oncol 2020; 10:1326. [PMID: 32903495 PMCID: PMC7435050 DOI: 10.3389/fonc.2020.01326] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022] Open
Abstract
Drug development targeting the most frequently mutation G12D of KRAS has great significance. As an attractive immunotherapy, cancer vaccines can overcome binding difficulties of small molecules; however, the weak immunogenicity and production difficulties of reported KRAS mutation vaccines limit their clinical application. To improve antigen-specific immune responses and Anti-Tumor effects on tumors expressing KRAS G12D mutation, we designed recombinant proteins containing KRAS peptide (amino acids 5–21) with G12D (called SP) in two forms: DTT-SP4 and DTSP. DTT-SP4 was constructed by fusing four copies of SP to the C-terminal of the translocation domain of diphtheria toxin (DTT), and DTSP was constructed by grafting SP onto DTT. The two vaccines in combination with aluminum hydroxide (Alum) and cytosine phosphoguanine (CpG) successfully induced conspicuous SP-specific humoral and cellular immune responses, and displayed prominent protective and therapeutic Anti-Tumor effects in mouse CT26 tumor models. Surprisingly, the DTSP-treated group displayed better Anti-Tumor effects in vivo compared with the DTT-SP4-treated and control groups. Moreover, 87.5 and 50% of DTSP-treated mice in the preventive and therapeutic models were tumor free, respectively. Notably, in the DTSP-treated group, the interferon-γ (IFN-γ) expression of T cells in vitro and the T-helper 1 (Th1)–related cytokine expression in tumor tissues indicated that the activated Th1 immune response may be involved in Anti-Tumor activity. Furthermore, DTSP treatment remarkably altered the subpopulation of T cells in splenocytes and tumor-infiltrating lymphocytes. The percentage of effector CD8+ T cells increased, whereas that of immunosuppressive CD4+Foxp3+ T cells remained reduced in the DTSP group. Dramatic tumor-inhibitory effects of DTSP, which is easily prepared, make it a more attractive strategy against KRAS G12D tumors.
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Affiliation(s)
- Yuhua Wan
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Gengchong Wang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Patrick Malonza Mwangi
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Huaman Cai
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Rongxiu Li
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,Shanghai HyCharm Inc., Shanghai, China.,Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
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21
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Li KY, Yuan JL, Trafton D, Wang JX, Niu N, Yuan CH, Liu XB, Zheng L. Pancreatic ductal adenocarcinoma immune microenvironment and immunotherapy prospects. Chronic Dis Transl Med 2020; 6:6-17. [PMID: 32226930 PMCID: PMC7096327 DOI: 10.1016/j.cdtm.2020.01.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Indexed: 02/08/2023] Open
Abstract
The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is non-immunogenic, which consists of the stellate cells, fibroblasts, immune cells, extracellular matrix, and some other immune suppressive molecules. This low tumor perfusion microenvironment with physical dense fibrotic stroma shields PDAC from traditional antitumor therapies like chemotherapy and various strategies that have been proven successful in other types of cancer. Immunotherapy has the potential to treat minimal and residual diseases and prevent recurrence with minimal toxicity, and studies in patients with metastatic and nonresectable disease have shown some efficacy. In this review, we highlighted the main components of the pancreatic tumor microenvironment, and meanwhile, summarized the advances of some promising immunotherapies for PDAC, including checkpoint inhibitors, chimeric antigen receptors T cells, and cancer vaccines. Based on our previous researches, we specifically discussed how granulocyte-macrophage colony stimulating factor based pancreatic cancer vaccine prime the pancreatic tumor microenvironment, and introduced some novel immunoadjuvants, like the stimulator of interferon genes.
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Affiliation(s)
- Ke-Yu Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Jia-Long Yuan
- School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Diego Trafton
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Jian-Xin Wang
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Hepatic-biliary-pancreatic Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Nan Niu
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China
| | - Chun-Hui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Xu-Bao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lei Zheng
- Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
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22
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Osipov A, Murphy A, Zheng L. From immune checkpoints to vaccines: The past, present and future of cancer immunotherapy. Adv Cancer Res 2019; 143:63-144. [PMID: 31202363 DOI: 10.1016/bs.acr.2019.03.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer is a worldwide medical problem with significant repercussions on individual patients and societies as a whole. In order to alter the outcomes of this deadly disease the treatment of cancer over the centuries has undergone a unique evolution. However, utilizing the best treatment modalities and achieving cures or long-term durable responses have been inconsistent and limited, that is until recently. Contemporary research has highlighted a fundamental gap in our understanding of how we approach treating cancer, by revealing the intricate relationship between the immune system and tumors. In this atmosphere, the growth of immunotherapy has not only forever changed our understanding of cancer biology, but the manner by which we treat patients. It's paradigm shifting success has led to the approval of over 10 different immunotherapeutic agents, including checkpoint inhibitors, vaccine-based therapies, oncolytic viruses and T cell directed therapies for nearly 20 different indications across countless tumor types. Despite the breakthroughs that have occurred in the field of immunotherapy, it has not been the panacea for all cancers. With a deeper understanding of the immune system we have been able to peer into tumor immune escape and therapy resistance. Simultaneously this understanding has paved the way for the investigation and development of novel immune system altering agents and combinatorial therapies. In this chapter we review the immune system and its intricate relationship with cancer, the evolution of immunotherapy, its current landscape, and future directions in the context of resistance mechanisms and the challenges faced by immunotherapy against cancer.
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Affiliation(s)
- Arsen Osipov
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Adrian Murphy
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lei Zheng
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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23
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Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer. Nat Commun 2019; 10:899. [PMID: 30796212 PMCID: PMC6385305 DOI: 10.1038/s41467-019-08782-1] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 01/24/2019] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8+ T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.
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24
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Abstract
Pancreatic cancer is resistant to the immunotherapy. This resistance is caused by any of the four immune "defects" that occur in pancreatic cancer, including lack of "high quality" T cells, stromal barriers to T cells getting access to tumor cells, immunosuppressive cells such as M2 macrophages, myeloid derivative suppressor cells, and T regulatory cells, in the tumor microenvironment of pancreatic cancer. One or more defects may occur in an individual pancreatic cancer. To overcome the resistance to the immunotherapy such as immune checkpoint inhibitors, a rational combination of agents that target multiple immune defects is highly demanded.
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Affiliation(s)
- Lei Zheng
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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25
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Reccia I, Kumar J, Habib N, Sodergren M. The use of radiofrequency ablation in pancreatic cancer in the midst of the dawn of immuno-oncology. Med Oncol 2018; 35:151. [PMID: 30284649 DOI: 10.1007/s12032-018-1209-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 09/26/2018] [Indexed: 02/06/2023]
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26
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Yegya-Raman N, Shah MM, Grandhi MS, Poplin E, August DA, Kennedy TJ, Malhotra U, Spencer KR, Carpizo DR, Jabbour SK. Adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma. ACTA ACUST UNITED AC 2018; 1. [PMID: 30687847 DOI: 10.21037/apc.2018.07.05] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.
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Affiliation(s)
- Nikhil Yegya-Raman
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Mihir M Shah
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Miral S Grandhi
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Elizabeth Poplin
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - David A August
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Timothy J Kennedy
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Usha Malhotra
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Kristen R Spencer
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Darren R Carpizo
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
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27
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Tian H, He Y, Song X, Jiang L, Luo J, Xu Y, Zhang W, Gao X, Yao W. Nitrated T helper cell epitopes enhance the immunogenicity of HER2 vaccine and induce anti-tumor immunity. Cancer Lett 2018; 430:79-87. [DOI: 10.1016/j.canlet.2018.05.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 05/06/2018] [Accepted: 05/15/2018] [Indexed: 01/27/2023]
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28
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Sonntag K, Hashimoto H, Eyrich M, Menzel M, Schubach M, Döcker D, Battke F, Courage C, Lambertz H, Handgretinger R, Biskup S, Schilbach K. Immune monitoring and TCR sequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized, neoepitope-derived multipeptide vaccines: a case report. J Transl Med 2018; 16:23. [PMID: 29409514 PMCID: PMC5801813 DOI: 10.1186/s12967-018-1382-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 01/10/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing. METHODS Vaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN-γ+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-γ-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization. RESULTS A peptide-specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRVα chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now. CONCLUSIONS Therapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial.
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Affiliation(s)
- Katja Sonntag
- Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany
| | - Hisayoshi Hashimoto
- Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany
| | - Matthias Eyrich
- Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Medical Center Würzburg, Josef-Schneider Street 2, 97080, Würzburg, Germany
| | - Moritz Menzel
- Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Paul-Ehrlich-Straße 23, 72076, Tübingen, Germany
| | - Max Schubach
- Institute for Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Dennis Döcker
- Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Paul-Ehrlich-Straße 23, 72076, Tübingen, Germany
| | - Florian Battke
- Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Paul-Ehrlich-Straße 23, 72076, Tübingen, Germany
| | - Carolina Courage
- Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00014, Helsinki, Finland
| | - Helmut Lambertz
- Klinikum Garmisch-Partenkirchen GmbH, Zentrum für Innere Medizin, 82467, Garmisch-Partenkirchen, Germany
| | - Rupert Handgretinger
- Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany
| | - Saskia Biskup
- Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Paul-Ehrlich-Straße 23, 72076, Tübingen, Germany
| | - Karin Schilbach
- Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, Hoppe-Seyler Street 1, 72076, Tübingen, Germany. .,University Children's Hospital, University Medical Center Tübingen, Hoppe-Seyler-Street 1, 72076, Tübingen, Germany.
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29
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Nishida S, Ishikawa T, Egawa S, Koido S, Yanagimoto H, Ishii J, Kanno Y, Kokura S, Yasuda H, Oba MS, Sato M, Morimoto S, Fujiki F, Eguchi H, Nagano H, Kumanogoh A, Unno M, Kon M, Shimada H, Ito K, Homma S, Oka Y, Morita S, Sugiyama H. Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study. Cancer Immunol Res 2018; 6:320-331. [PMID: 29358173 DOI: 10.1158/2326-6066.cir-17-0386] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/17/2017] [Accepted: 01/09/2018] [Indexed: 11/16/2022]
Abstract
We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01- or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320-31. ©2018 AACR.
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Affiliation(s)
- Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Takeshi Ishikawa
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shinichi Egawa
- Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | | | - Jun Ishii
- Division of General and Gastroenterological Surgery, Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yoshihide Kanno
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Satoshi Kokura
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroaki Yasuda
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mari Saito Oba
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Maho Sato
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Soyoko Morimoto
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masanori Kon
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Hideaki Shimada
- Division of General and Gastroenterological Surgery, Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan
| | - Kei Ito
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Sadamu Homma
- Division of Oncology, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshihiro Oka
- Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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30
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Schmitz-Winnenthal FH, Hohmann N, Schmidt T, Podola L, Friedrich T, Lubenau H, Springer M, Wieckowski S, Breiner KM, Mikus G, Büchler MW, Keller AV, Koc R, Springfeld C, Knebel P, Bucur M, Grenacher L, Haefeli WE, Beckhove P. A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. Oncoimmunology 2018; 7:e1303584. [PMID: 29632710 DOI: 10.1080/2162402x.2017.1303584] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 02/24/2017] [Accepted: 03/01/2017] [Indexed: 12/17/2022] Open
Abstract
VXM01 is a first-in-kind orally applied tumor vaccine based on live attenuated Salmonella typhi carrying an expression plasmid encoding VEGFR2, an antigen expressed on tumor vasculature and a stable and accessible target for anti-angiogenic intervention. A recent randomized, placebo-controlled, phase I dose-escalation trial in advanced pancreatic cancer patients demonstrated safety, immunogenicity and transient, T-cell response-related anti-angiogenic activity of four priming vaccinations applied within one week. We here evaluated whether monthly boost vaccinations are safe and can sustain increased frequencies of vaccine-specific T cells. Patients with advanced pancreatic cancer were randomly assigned at a ratio of 2:1 to priming with VXM01 followed by up to six monthly boost vaccinations, or placebo treatment. Vaccinations were applied orally at two alternative doses of either 106 colony-forming units (CFU) or 107 CFU, and concomitant treatment with standard-of-care gemcitabine during the priming phase, and any treatment thereafter, was allowed in the study. Immunomonitoring involved interferon-gamma (IFNγ) ELIspot analysis with long overlapping peptides spanning the entire VEGFR2 sequence. A total of 26 patients were treated. Treatment-related adverse events preferentially associated with VXM01 were decreases in lymphocyte numbers in the blood, increased frequencies of neutrophils and diarrhea. Eight out of 16 patients who received at least one boosting vaccination responded with pronounced, i.e. at least 3-fold, increase in VEGFR2-specific T cell response over baseline levels. In the VXM01 vaccination group, VEGFR2-specific T cells peaked preferentially during the boosting phase with an average 4-fold increase over baseline levels. In conclusion, prime/boost vaccination with VXM01 was safe and immunogenic and increased vaccine specific T cell responses compared with placebo treatment.
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Affiliation(s)
| | - Nicolas Hohmann
- Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Schmidt
- Department of General, Abdominal and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Lilli Podola
- Regensburg Center for Interventional Immunology (RCI), University Hospital Regensburg, Regensburg, Germany.,Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany
| | - Tobias Friedrich
- Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany
| | | | | | | | | | - Gerd Mikus
- Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Markus W Büchler
- Department of General, Abdominal and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Ruhan Koc
- Department of General, Abdominal and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Phillip Knebel
- Department of General, Abdominal and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Mariana Bucur
- Regensburg Center for Interventional Immunology (RCI), University Hospital Regensburg, Regensburg, Germany
| | - Lars Grenacher
- Diagnostic Munich, Diagnostic Prevention and Imaging Center, Munich, Germany
| | - Walter E Haefeli
- Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Philipp Beckhove
- Regensburg Center for Interventional Immunology (RCI), University Hospital Regensburg, Regensburg, Germany.,Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany
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31
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Affiliation(s)
- Thaiz Rivera Vargas
- Centre de Recherche; INSERM U1231; Facultés de Médecine et de Pharmacie; Dijon France
- Faculté de Médecine; Université de Bourgogne Franche comté; Dijon France
| | - Lionel Apetoh
- Centre de Recherche; INSERM U1231; Facultés de Médecine et de Pharmacie; Dijon France
- Faculté de Médecine; Université de Bourgogne Franche comté; Dijon France
- Centre Georges François Leclerc; Dijon France
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32
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Bolhassani A, Naderi N, Soleymani S. Prospects and progress of Listeria-based cancer vaccines. Expert Opin Biol Ther 2017; 17:1389-1400. [PMID: 28823183 DOI: 10.1080/14712598.2017.1366446] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION The development of an effective therapeutic vaccine to induce cancer-specific immunity remains problematic. Recently, a species of intracellular pathogen known as Listeria monocytogenes (Lm) has been used to transfer DNA, RNA and proteins into tumour cells as well as elicit an immune response against tumour-specific antigens. Areas covered: Herein, the authors provide the mechanisms of different Listeria monocytogenes strains, which are potential therapeutic cancer vaccine vectors, in addition to their preclinical and clinical development. They also speculate on the future of Lm-based tumour immunotherapies. The article is based on literature published on PubMed and data reported in clinical trials. Expert opinion: Attenuated strains of Listeria monocytogenes have safely been applied as therapeutic bacterial vectors for the delivery of cancer vaccines. These vectors stimulate MHCI and MHCII pathways as well as the proliferation of antigen-specific T lymphocytes. Several preclinical studies have demonstrated the potency of Lm in intracellular gene and protein delivery in vitro and in vivo. They have also indicated safety and efficiacy in clinical trials. Readers should be aware that the ability of attenuated Lm strains to induce potent immune responses depends on the type of deleted or inactivated Lm virulent gene or genes.
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Affiliation(s)
- Azam Bolhassani
- a Department of Hepatitis and AIDS , Pasteur Institute of Iran , Tehran , Iran
| | - Niloofar Naderi
- a Department of Hepatitis and AIDS , Pasteur Institute of Iran , Tehran , Iran
| | - Sepehr Soleymani
- a Department of Hepatitis and AIDS , Pasteur Institute of Iran , Tehran , Iran
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33
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Skelton RA, Javed A, Zheng L, He J. Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors. J Surg Oncol 2017. [PMID: 28628715 DOI: 10.1002/jso.24642] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors.
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Affiliation(s)
- Richard A Skelton
- The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ammar Javed
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lei Zheng
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jin He
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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34
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Zhang B, Dong Y, Liu J, Lian Z, Liang L, Chen W, Luo X, Pei S, Mo X, Zhang L, Huang W, Ouyang F, Guo B, Liang C, Zhang S. Immunotherapy for patients with advanced pancreatic carcinoma: a promising treatment. Oncotarget 2017; 8:5703-5716. [PMID: 27992378 PMCID: PMC5351583 DOI: 10.18632/oncotarget.13968] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 12/12/2016] [Indexed: 12/11/2022] Open
Abstract
There are limited data on the safety and efficacy of immunotherapy for patients with advanced pancreatic cancer (APC). A meta-analysis of single-arm trials is proposed to assess the efficacy and safety of immunotherapy for APC. Eighteen relevant studies involving 527 patients were identified. The pooled disease control rate (DCR), overall survival (OS), progression free survival (PFS), and 1-year survival rate were estimated as 59.32%, 7.90 months, 4.25 months, and 30.12%, respectively. Subgroup analysis showed that the pooled OS, PFS, and 1-year survival rate were significantly higher for autologous activated lymphocyte therapy compared with peptide-based vaccine therapy (OS: 8.28 months vs. 7.40 months; PFS: 6.04 months vs. 3.86 months; 1-year survival rate: 37.17% vs. 19.74%). Another subgroup analysis demonstrated that the pooled endpoints were estimated as obviously higher for immunotherapy plus chemotherapy compared with immunotherapy alone (DCR: 62.51% vs. 47.63%; OS: 8.67 months vs. 4.91 months; PFS: 4.91 months vs. 3.34 months; 1-year survival rate: 32.32% vs. 21.43%). Of the included trials, seven trials reported no treatment related adverse events , five trials reported (16.6 ± 3.9) % grade 3 adverse events and no grade 4 adverse events. In conclusion, immunotherapy is safe and effective in the treatment of APC.
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Affiliation(s)
- Bin Zhang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yuhao Dong
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Jing Liu
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Zhouyang Lian
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Long Liang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Wenbo Chen
- Department of Radiology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, P.R. China
| | - Xiaoning Luo
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Shufang Pei
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Xiaokai Mo
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Lu Zhang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Wenhui Huang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- School of medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Fusheng Ouyang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Baoliang Guo
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Changhong Liang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
| | - Shuixing Zhang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
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Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. Cancer Gene Ther 2016; 23:278-83. [PMID: 27468808 DOI: 10.1038/cgt.2016.31] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 05/14/2016] [Accepted: 06/15/2016] [Indexed: 01/04/2023]
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36
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De Souza A, Irfan K, Masud F, Saif MW. Diabetes Type 2 and Pancreatic Cancer: A History Unfolding. JOP : JOURNAL OF THE PANCREAS 2016; 17:144-148. [PMID: 29568247 PMCID: PMC5860818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Pancreatic Cancer is the fourth cause of cancer-related deaths in the United States. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent literature suggests that diabetes mellitus type 2 is a risk factor, a manifestation and a prognostic factor for pancreatic cancer. This article is intended to clarify the evidence about diabetes as a risk factor for pancreatic cancer.
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Affiliation(s)
- Andre De Souza
- Department of Hematology and Oncology, Tufts Medical Center, Boston, MA, USA
| | - Khawaja Irfan
- Department of Endocrinology and Metabolism, Services Institute of Medical Sciences, Lahore, Pakistan
| | - Faisal Masud
- King Edward Medical University, Lahore, Pakistan
| | - Muhammad Wasif Saif
- Department of Hematology and Oncology, Tufts Medical Center, Boston, MA, USA
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37
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Schnurr M, Duewell P, Bauer C, Rothenfusser S, Lauber K, Endres S, Kobold S. Strategies to relieve immunosuppression in pancreatic cancer. Immunotherapy 2016; 7:363-76. [PMID: 25917628 DOI: 10.2217/imt.15.9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Despite continuous progress in the understanding of deregulated pathways in pancreatic cancer cells and development of targeted therapies, therapeutic advances with clinical benefit have been scarce over the last decades. The recent success of immunotherapy for some solid cancers has fueled optimism that this approach might also work for pancreatic cancer. However, a highly immunosuppressive microenvironment mediated by tumor, stromal and immune cells creates a major hurdle for immunotherapy. Mouse models have helped to unravel critical immunosuppressive mechanisms that could serve as novel therapeutic targets. Here we review new promising strategies that alone or in combination with other modalities, such as chemotherapy or irradiation, have the potential to lead to tumor immune control and finally better clinical outcome.
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Affiliation(s)
- Max Schnurr
- Division of Clinical Pharmacology & Center for Integrated Protein Science Munich (CIPSM), Klinikum der Universität München, Munich, Germany
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38
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Xue M, Sun H, Cao Y, Wang G, Meng Y, Wang D, Hong Y. Mulberry leaf polysaccharides modulate murine bone-marrow-derived dendritic cell maturation. Hum Vaccin Immunother 2016; 11:946-50. [PMID: 25830302 DOI: 10.1080/21645515.2015.1011977] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Various components of mulberry leaves, such as iminosugars, flavonoids and polysaccharides, have been reported to exert anti-diabetic activity. The purpose of our present study was to examine the modulating effect of mulberry leaf polysaccharides (MLPs) on murine bone-marrow-derived dendritic cells (BMDCs). The ultrastructure, phenotype and functional maturation of BMDCs were studied using transmission electron microscopy (TEM), flow cytometry (FCM), and tested for phagocytosis, acid phosphatase (ACP) activity using an enzyme linked immunosorbent assay (ELISA). Our results demonstrated that MLPs could markedly induce BMDC maturation by up-regulating the expression of membrane phenotypic markers, such as CD80, CD86, CD83,CD40, and MHC II, down-regulating phagocytosis and ACP activity, and by enhancing the production of interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) secreted by BMDCs. We therefore concluded that MLPs can positively modulate BMDCs.
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Key Words
- ACP, acidic phosphatase
- BMDCs, bone-marrow-derived dendritic cells
- DAB, 3, 3′-diaminobenzidine
- FCM, flow cytometry
- LPS, lipopolysaccharide
- MACS, magnetic activated cell sorting
- MLP, mulberry leaf polysaccharides
- MTS, methyl tolyl sulfide
- TEM, transmission electron microscopy
- bone-marrow-derived dendritic cells
- immunoregulation
- maturation
- mulberry leaf polysaccharides
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Affiliation(s)
- Ming Xue
- a Department of Endodontics ; School of Stomatology; China Medical University ; Shenyang , China
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Chand S, O'Hayer K, Blanco FF, Winter JM, Brody JR. The Landscape of Pancreatic Cancer Therapeutic Resistance Mechanisms. Int J Biol Sci 2016; 12:273-82. [PMID: 26929734 PMCID: PMC4753156 DOI: 10.7150/ijbs.14951] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients' PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post-transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease.
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Affiliation(s)
- Saswati Chand
- 1. Department of Surgery, The Jefferson Pancreas, Biliary, and Related Cancer Center
| | - Kevin O'Hayer
- 1. Department of Surgery, The Jefferson Pancreas, Biliary, and Related Cancer Center;; 2. Department of Medical Oncology, and the; 3. Department of Pharmacology & Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia PA
| | - Fernando F Blanco
- 1. Department of Surgery, The Jefferson Pancreas, Biliary, and Related Cancer Center;; 3. Department of Pharmacology & Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia PA
| | - Jordan M Winter
- 1. Department of Surgery, The Jefferson Pancreas, Biliary, and Related Cancer Center
| | - Jonathan R Brody
- 1. Department of Surgery, The Jefferson Pancreas, Biliary, and Related Cancer Center
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Zhang L, Zhu W, Li J, Yang X, Ren Y, Niu J, Pang Y. Clinical outcome of immunotherapy with dendritic cell vaccine and cytokine-induced killer cell therapy in hepatobiliary and pancreatic cancer. Mol Clin Oncol 2015; 4:129-133. [PMID: 26870371 DOI: 10.3892/mco.2015.660] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 10/19/2015] [Indexed: 12/17/2022] Open
Abstract
The aim of this study was to determine the therapeutic effects of adoptive immunotherapy following dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell therapy and evaluate its cytotoxicity, survival benefits and quality of life (QOL) changes in patients with hepatobiliary and pancreatic cancer (HPC). We performed a retrospective analysis of 407 clinical cases, including 77 patients with HPC who received immunotherapy with DC vaccine and CIK cells (I group) and 330 patients with similar characteristics who underwent baseline treatment but did not receive immunotherapy [non-immunotherapy (NI) group)] as the control group. After a follow-up period of 294±207.5 days, the median survival time (MST) of the two groups was compared using the Kaplan-Meier method. In the I group, 61% of the patients developed a positive, delayed-type hypersensitivity response and 65% of the patients exhibited an improvement in QOL. The most notable adverse events included fever (28%), insomnia (25%), anorexia (17%), skin rash (12%) and arthralgia (31%). No severe toxicities were observed in patients in the I group; in addition, the MST was significantly longer in the I group compared with that in the NI group (P=0.014). Thus, the DC vaccine and CIK cell therapy was associated with mild adverse effects, but was able to induce an immune response and effectively eliminate tumor cells, thereby improving the QOL and prolonging the MST of the patients.
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Affiliation(s)
- Lihong Zhang
- School of Medicine, NanKai University, Tianjin 300071, P.R. China
| | - Wei Zhu
- Graduate School of Tianjin Medical University, Tianjin 300070, P.R. China
| | - Jiali Li
- Department of Oncology, Tianjin Union Medicine Centre, Tianjin 300121, P.R. China
| | - Xuejing Yang
- Department of Oncology, Tianjin Union Medicine Centre, Tianjin 300121, P.R. China
| | - Yanjie Ren
- Department of Oncology, Tianjin Union Medicine Centre, Tianjin 300121, P.R. China
| | - Jingxiu Niu
- Department of Oncology, Tianjin Union Medicine Centre, Tianjin 300121, P.R. China
| | - Yan Pang
- Department of Oncology, Tianjin Union Medicine Centre, Tianjin 300121, P.R. China
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Kleponis J, Skelton R, Zheng L. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors. Cancer Biol Med 2015; 12:201-8. [PMID: 26487965 PMCID: PMC4607816 DOI: 10.7497/j.issn.2095-3941.2015.0046] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.
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Affiliation(s)
- Jennifer Kleponis
- 1 Department of Oncology, Department of Surgery, The Sidney Kimmel Comprehensive Cancer, The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA ; 2 Masters of Health Science Program in Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21287, USA
| | - Richard Skelton
- 1 Department of Oncology, Department of Surgery, The Sidney Kimmel Comprehensive Cancer, The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA ; 2 Masters of Health Science Program in Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21287, USA
| | - Lei Zheng
- 1 Department of Oncology, Department of Surgery, The Sidney Kimmel Comprehensive Cancer, The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA ; 2 Masters of Health Science Program in Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21287, USA
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Sclafani F, Iyer R, Cunningham D, Starling N. Management of metastatic pancreatic cancer: Current treatment options and potential new therapeutic targets. Crit Rev Oncol Hematol 2015; 95:318-36. [PMID: 25921418 DOI: 10.1016/j.critrevonc.2015.03.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 03/18/2015] [Accepted: 03/31/2015] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is a malignancy with a poor prognosis, with the majority of patients diagnosed with advanced disease on presentation. Treatment options remain limited with little progress over the last 40 years. This review will focus on the current management of metastatic pancreatic ductal adenocarcinoma, with a discussion of new and future treatment strategies based on an improved understanding of tumour biology and mechanisms of pathogenesis.
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Affiliation(s)
| | - Ridhima Iyer
- The Royal Marsden NHS Foundation Trust, London and Surrey, UK
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43
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Markman JL, Shiao SL. Impact of the immune system and immunotherapy in colorectal cancer. J Gastrointest Oncol 2015; 6:208-23. [PMID: 25830040 DOI: 10.3978/j.issn.2078-6891.2014.077] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/20/2014] [Indexed: 12/12/2022] Open
Abstract
The development of cancer is a multi-step process involving the gradual loss of regulation over the growth and functional capabilities of normal cells. Much research has been focused on the numerous cell intrinsic factors that govern this process; however, recent attention has turned to understanding the cell extrinsic factors in the tumor microenvironment that appear equally critical to the progression and treatment of cancer. One critical component of the tumor microenvironment is the immune system and it has become increasingly evident that the immune system plays an integral role in preventing and promoting the development of cancer. Understanding the immune cell types and pathways involved in this process has enabled the development of novel biomarkers for prognosis and accelerated the development of immune-based therapeutics, both of which have the potential to forever change the treatment paradigms for colorectal cancer (CRC). In this review, we discuss the impact of the immune system on the initiation, progression and treatment of cancer, specifically focusing on CRC.
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Affiliation(s)
- Janet L Markman
- 1 Department of Biomedical Sciences, 2 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Stephen L Shiao
- 1 Department of Biomedical Sciences, 2 Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Dillon AB, Lin K, Kwong A, Ortiz S. Immunotherapy in Melanoma, Gastrointestinal (GI), and Pulmonary Malignancies. AIMS Public Health 2015; 2:86-114. [PMID: 29546098 PMCID: PMC5690372 DOI: 10.3934/publichealth.2015.1.86] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Accepted: 03/20/2015] [Indexed: 12/14/2022] Open
Abstract
Oncologic immunotherapy involves stimulating the immune system to more effectively identify and eradicate tumor cells that have successfully adapted to survive the body's natural immune defenses. Immunotherapy has shown great promise thus far by prolonging the lives of patients with a variety of malignancies, and has added a crucial new set of tools to the oncologists' armamentarium. The aim of this paper is to provide an overview of immunotherapy treatment options that are currently available and under active research for melanoma, gastrointestinal (esophageal, gastric, pancreatic, and colorectal), and pulmonary malignancies. Potential biomarkers that may predict favorable responses to immunotherapies are discussed where applicable, as are future avenues of research in this rapidly evolving field.
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Affiliation(s)
- Alexander B. Dillon
- Mount Zion Cancer Research Center, Department of Dermatology, University of California San Francisco, CA 94141, USA
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45
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Trials of vaccines for pancreatic ductal adenocarcinoma: Is there any hope of an improved prognosis? Surg Today 2015; 46:139-48. [PMID: 25649538 DOI: 10.1007/s00595-015-1120-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 01/06/2015] [Indexed: 02/06/2023]
Abstract
Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.
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46
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Di Caro G, Castino GF, Bergomas F, Cortese N, Chiriva-Internati M, Grizzi F, Marchesi F. Immune-based therapies in pancreatic and colorectal cancers and biomarkers of responsiveness. Expert Rev Anticancer Ther 2014; 14:1219-28. [PMID: 25222571 DOI: 10.1586/14737140.2014.947277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immune-based strategies are the most promising treatments to improve cancer disease control. Early clinical trials are ongoing to test the safety and feasibility of immune-based therapies for gastrointestinal cancers. However, to date, immunotherapy has been only an experimental option for these diseases and a better understanding of their molecular, cellular, structural and clinical dissimilarities is crucial in the generation of tailored immunotherapeutic treatments. In this review, we will summarize the key mechanisms that regulate the action of immune system in cancer and the different immune-based approaches aimed at improving disease control in patients with advanced disease. We will then move on to discussing the current immunotherapeutic approaches in two types of gastrointestinal (colo-rectal and pancreatic) cancers, whose immune microenvironment has been lately object of intense analyses and has emerged as an important determinant of clinical outcome.
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Affiliation(s)
- Giuseppe Di Caro
- Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy
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47
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Jia L, Gao X, Wang Y, Yao N, Zhang X. Structural, phenotypic and functional maturation of bone marrow dendritic cells (BMDCs) induced by Chitosan (CTS). Biologicals 2014; 42:334-8. [PMID: 25225119 DOI: 10.1016/j.biologicals.2014.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 07/15/2014] [Accepted: 07/17/2014] [Indexed: 01/23/2023] Open
Abstract
The objective of the present work was to explore the effect of CTS on structural, phenotypic and functional maturation of murine bone marrow derived dendritic cells (BMDCs). The maturity of BMDCs post treatment with CTS was evaluated using transmission electron microscopy (TEM) for structure changes, flow cytometry (FCM) for changes of key surface molecules, FITC-dextran bio-assay for phagocytosis, test of acid phosphatase activity (ACP) for biochemical changes and enzyme linked immunosorbent assay (ELISA) for cytokine level. We found that CTS downregulated the numbers of phagosomes inside the BMDCs, up-regulated the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs, decreased activity of ACP and phagocytosis by BMDCs, and induced production of higher levels of IL-12 and TNF-α. It was therefore confirmed that CTS could effectively promote the maturation of BMDCs. Our study provided more detailed evidence and rationale to support the application of CTS as an immune stimulator for enhancing host immunity and as an adjuvant in the design of DC-based vaccines.
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Affiliation(s)
- Lihui Jia
- Department of Stomatology, General Hospital of Shenyang Military Area Command, Shenyang 110084, China
| | - Xinghua Gao
- Department of Dermatology, No.1 Hospital, China Medical University, Shenyang 110001, China
| | - Yiqing Wang
- Department of Stomatology, General Hospital of Shenyang Military Area Command, Shenyang 110084, China
| | - Na Yao
- Department of Stomatology, General Hospital of Shenyang Military Area Command, Shenyang 110084, China
| | - Xiaodong Zhang
- Department of Stomatology, General Hospital of Shenyang Military Area Command, Shenyang 110084, China.
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