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Shakerian N, Tafazoli A, Razavinia A, Sadrzadeh Aghajani Z, Bana N, Mard-Soltani M, Khalesi B, Hashemi ZS, Khalili S. Current Understanding of Therapeutic and Diagnostic Applications of Exosomes in Pancreatic Cancer. Pancreas 2025; 54:e255-e267. [PMID: 39661050 DOI: 10.1097/mpa.0000000000002414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]
Abstract
ABSTRACT Unusual symptoms, rapid progression, lack of reliable early diagnostic biomarkers, and lack of efficient treatment choices are the ongoing challenges of pancreatic cancer. Numerous research studies have demonstrated the correlation between exosomes and various aspects of pancreatic cancer. In light of these facts, exosomes possess the potential to play functional roles in the treatment, prognosis, and diagnosis of the pancreatic cancer. In the present study, we reviewed the most recent developments in approaches for exosome separation, modification, monitoring, and communication. Moreover, we discussed the clinical uses of exosomes as less invasive liquid biopsies and drug carriers and their contribution to the control of angiogenic activity of pancreatic cancer. Better investigation of exosome biology would help to effectively engineer therapeutic exosomes with certain nucleic acids, proteins, and even exogenous drugs as their cargo. Circulating exosomes have shown promise as reliable candidates for pancreatic cancer early diagnosis and monitoring in high-risk people without clinical cancer manifestation. Although we have tried to reflect the status of exosome applications in the treatment and detection of pancreatic cancer, it is evident that further studies and clinical trials are required before exosomes may be employed as a routine therapeutic and diagnostic tools for pancreatic cancer.
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Affiliation(s)
- Neda Shakerian
- From the Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful
| | - Aida Tafazoli
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz
| | - Amir Razavinia
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, IR
| | | | - Nikoo Bana
- Kish International Campus, University of Teheran
| | - Maysam Mard-Soltani
- From the Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization, Karaj
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
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2
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Matsumoto K, Kato H, Tsutsumi K, Otsuka M. Current status of endoscopic ultrasound-guided antitumor treatment for pancreatic cancer. Dig Endosc 2025; 37:18-28. [PMID: 38752622 PMCID: PMC11718125 DOI: 10.1111/den.14815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/15/2024] [Indexed: 01/11/2025]
Abstract
Endoscopic ultrasound (EUS) was developed in the 1990s and has significantly transformed pancreatic tumor diagnosis. Subsequently, EUS has rapidly shifted from being a purely diagnostic procedure to being used in a wide range of interventional procedures. Recently, new therapeutic techniques, such as EUS-guided fine needle injection (EUS-FNI) or radiofrequency ablation (RFA), have been developed to deliver various antitumor agents. Despite technological advancements, pancreatic cancer (PC) has a poor prognosis and improvements in treatment outcomes are urgently required. One of the reasons for the limited response to antitumor agents in PC is the abundant desmoplasia and hypovascular nature of the tumor, complicating drug delivery into the tumor. Thus, changing the tumor microenvironment may be important to enhance the effectiveness of chemotherapy, and direct injection of antitumor agents into the tumor under EUS guidance can help overcome treatment challenges in PC. Treatment approaches using the EUS-FNI or RFA technique are expected to further improve the prognosis of PC. Therefore, this study reviewed the existing literature on EUS-guided antitumor therapy, specifically highlighting its application in PC to address the current challenges and to identify potential advancements in the field.
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Affiliation(s)
- Kazuyuki Matsumoto
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Hironari Kato
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Koichiro Tsutsumi
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Motoyuki Otsuka
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
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3
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Harne PS, Harne V, Wray C, Thosani N. Endoscopic innovations in diagnosis and management of pancreatic cancer: a narrative review and future directions. Therap Adv Gastroenterol 2024; 17:17562848241297434. [PMID: 39664230 PMCID: PMC11632891 DOI: 10.1177/17562848241297434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 10/15/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic cancer serves as the third leading cause of cancer-associated morbidity and mortality in the United States, with a 5-year survival rate of only 12% with an expected increase in incidence and mortality in the coming years. Pancreatic ductal adenocarcinomas constitute most pancreatic malignancies. Certain genetic syndromes, including Lynch syndrome, hereditary breast and ovarian cancer syndrome, hereditary pancreatitis, familial adenomatous polyposis, Peutz-Jeghers syndrome, familial pancreatic cancer mutation, and ataxia telangiectasia, confer a significantly higher risk. Screening for pancreatic malignancies currently targets patients with germline mutations or those with significant family history. Screening the general population is not currently viable owing to overall low incidence and lack of specific tests. Endoscopic ultrasound (EUS) and its applied advances are increasingly being used for surveillance, diagnosis, and management of pancreatic malignancies and have now become an indispensable tool in their management. For patients with risk factors, EUS in combination with magnetic resonance imaging/magnetic resonance cholangiopancreatography is used for screening. The role of endoscopic modalities has been expanding with the increased utilization of endoscopic retrograde cholangiopancreatography, EUS-directed therapies include EUS-guided fine-needle aspiration and EUS-fine-needle biopsy (FNB). EUS combined with FNB has the highest specificity and sensitivity for detecting pancreatic cancer amongst available modalities. Studies also recognize that artificial intelligence assisted EUS in the early detection of pancreatic cancer. At the same time, surgical resection has been historically considered the only curative treatment for pancreatic cancer, over 80% of patients present with unresectable disease. We also discuss EUS-guided therapies of physicochemicals (radiofrequency ablation, brachytherapy, and intratumor chemotherapy), biological agents (gene therapies and oncolytic viruses), and immunotherapy. We aim to perform a detailed review of the current burden, risk factors, role of screening, diagnosis, and endoscopic advances in the treatment modalities available for pancreatic cancer.
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Affiliation(s)
- Prateek Suresh Harne
- Division of Gastroenterology, Allegheny Health Network, Pittsburgh, PA 15212, USA
| | - Vaishali Harne
- Division of Pediatric Gastroenterology, The University of Texas
- Health Science Center and McGovern School of Medicine, Houston, TX, USA
| | - Curtis Wray
- Department of Surgery, The University of Texas Health Science Center and McGovern School of Medicine, Houston, TX, USA
| | - Nirav Thosani
- Department of Surgery and Interventional Gastroenterology, The University of Texas
- Health Science Center and McGovern School of Medicine, Houston, TX, USA
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Omole AO, Zhao Z, Chang-Liao S, de Oliveira JFA, Boone CE, Sutorus L, Sack M, Varner J, Fiering SN, Steinmetz NF. Virus nanotechnology for intratumoural immunotherapy. NATURE REVIEWS BIOENGINEERING 2024; 2:916-929. [PMID: 39698315 PMCID: PMC11655125 DOI: 10.1038/s44222-024-00231-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 12/20/2024]
Abstract
Viruses can be designed to be tools and carrier vehicles for intratumoural immunotherapy. Their nanometre-scale size and shape allow for functionalization with or encapsulation of medical cargoes and tissue-specific ligands. Importantly, immunotherapies may particularly benefit from the inherent immunomodulatory properties of viruses. For example, mammalian viruses have already been tested for oncolytic virotherapy, and bacteriophages and plant viruses can be engineered for immunotherapeutic treatment approaches. In this Review, we discuss how viruses - including oncolytic viruses, immunomodulatory plant viruses and bacteriophages - and virus-like particles can be designed for intratumoural immunotherapy to elicit anti-tumour immunity and induce systemic anti-tumour responses at distant non-injected sites. We further highlight the engineering of viruses and virus-like particles as drug-delivery systems, and outline key translational challenges and clinical opportunities.
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Affiliation(s)
- Anthony O. Omole
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Zhongchao Zhao
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Sabrina Chang-Liao
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Jessica Fernanda Affonso de Oliveira
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Christine E. Boone
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Lucas Sutorus
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | | | - Judith Varner
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Center for Engineering in Cancer, Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - Steven N. Fiering
- Department of Microbiology and Immunology, Dartmouth Cancer Center, Dartmouth Geisel School of Medicine and Dartmouth-Hitchock Health, Lebanon, NH, USA
| | - Nicole F. Steinmetz
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, CA, USA
- Shu and K. C. Chien and Peter Farrell Collaboratory, University of California, San Diego, La Jolla, CA, USA
- Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Center for Engineering in Cancer, Institute of Engineering Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Radiology, University of California, San Diego, La Jolla, CA, USA
- Institute for Materials Discovery and Design, University of California, San Diego, La Jolla, CA, USA
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5
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Phan T, Fan D, Melstrom LG. Developing Vaccines in Pancreatic Adenocarcinoma: Trials and Tribulations. Curr Oncol 2024; 31:4855-4884. [PMID: 39329989 PMCID: PMC11430674 DOI: 10.3390/curroncol31090361] [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: 06/19/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic adenocarcinoma represents one of the most challenging malignancies to treat, with dismal survival rates despite advances in therapeutic modalities. Immunotherapy, particularly vaccines, has emerged as a promising strategy to harness the body's immune system in combating this aggressive cancer. This abstract reviews the trials and tribulations encountered in the development of vaccines targeting pancreatic adenocarcinoma. Key challenges include the immunosuppressive tumor microenvironment, the heterogeneity of tumor antigens, and a limited understanding of immune evasion mechanisms employed by pancreatic cancer cells. Various vaccine platforms, including peptide-based, dendritic cell-based, and viral vector-based vaccines, have been explored in preclinical and clinical settings. However, translating promising results from preclinical models to clinical efficacy has proven elusive. In recent years, mRNA vaccines have emerged as a promising immunotherapeutic strategy in the fight against various cancers, including pancreatic adenocarcinoma. We will discuss the potential applications, opportunities, and challenges associated with mRNA vaccines in pancreatic cancer treatment.
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Affiliation(s)
- Thuy Phan
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Darrell Fan
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Laleh G. Melstrom
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA;
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6
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Yuan Z, Zhang Y, Wang X, Wang X, Ren S, He X, Su J, Zheng A, Guo S, Chen Y, Deng S, Wu X, Li M, Du F, Zhao Y, Shen J, Wang Z, Xiao Z. The investigation of oncolytic viruses in the field of cancer therapy. Front Oncol 2024; 14:1423143. [PMID: 39055561 PMCID: PMC11270537 DOI: 10.3389/fonc.2024.1423143] [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: 04/25/2024] [Accepted: 06/26/2024] [Indexed: 07/27/2024] Open
Abstract
Oncolytic viruses (OVs) have emerged as a potential strategy for tumor treatment due to their ability to selectively replicate in tumor cells, induce apoptosis, and stimulate immune responses. However, the therapeutic efficacy of single OVs is limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). To overcome these challenges, engineering OVs has become an important research direction. This review focuses on engineering methods and multi-modal combination therapies for OVs aimed at addressing delivery barriers, viral phagocytosis, and antiviral immunity in tumor therapy. The engineering approaches discussed include enhancing in vivo immune response, improving replication efficiency within the tumor cells, enhancing safety profiles, and improving targeting capabilities. In addition, this review describes the potential mechanisms of OVs combined with radiotherapy, chemotherapy, cell therapy and immune checkpoint inhibitors (ICIs), and summarizes the data of ongoing clinical trials. By continuously optimizing engineering strategies and combination therapy programs, we can achieve improved treatment outcomes and quality of life for cancer patients.
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Affiliation(s)
- Zijun Yuan
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Anfu Zheng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sipeng Guo
- Research And Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Zechen Wang
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
| | - Zhangang Xiao
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Department of Pharmacology, School of Pharmacy, Sichuan College of Traditional Chinese Medicine, Mianyang, China
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7
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Zheng R, Liu X, Zhang Y, Liu Y, Wang Y, Guo S, Jin X, Zhang J, Guan Y, Liu Y. Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application. Front Immunol 2024; 15:1383978. [PMID: 38756774 PMCID: PMC11096556 DOI: 10.3389/fimmu.2024.1383978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Pancreatic cancer is a highly aggressive malignant tumor, that is becoming increasingly common in recent years. Despite advances in intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted therapy, the overall survival rate has not significantly improved in patients with pancreatic cancer. This may be attributed to the insidious onset, unknown pathophysiology, and poor prognosis of the disease. It is therefore essential to identify and develop more effective and safer treatments for pancreatic cancer. Tumor immunotherapy is the new and fourth pillar of anti-tumor therapy after surgery, radiotherapy, and chemotherapy. Significant progress has made in the use of immunotherapy for a wide variety of malignant tumors in recent years; a breakthrough has also been made in the treatment of pancreatic cancer. This review describes the advances in immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus, and matrix-depletion therapies for the treatment of pancreatic cancer. At the same time, some new potential biomarkers and potential immunotherapy combinations for pancreatic cancer are discussed. The molecular mechanisms of various immunotherapies have also been elucidated, and their clinical applications have been highlighted. The current challenges associated with immunotherapy and proposed strategies that hold promise in overcoming these limitations have also been discussed, with the aim of offering new insights into immunotherapy for pancreatic cancer.
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Affiliation(s)
- Rui Zheng
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaobin Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Yongxian Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yaping Wang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Shutong Guo
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaoyan Jin
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Jing Zhang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yuehong Guan
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yusi Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
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8
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Vargas A, Dutta P, Carpenter ES, Machicado JD. Endoscopic Ultrasound-Guided Ablation of Premalignant Pancreatic Cysts and Pancreatic Cancer. Diagnostics (Basel) 2024; 14:564. [PMID: 38473035 DOI: 10.3390/diagnostics14050564] [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: 01/28/2024] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
Pancreatic cancer is on the rise and expected to become the second leading cause of cancer-related death by 2030. Up to a one-fifth of pancreatic cancers may arise from mucinous pancreatic cysts, which are frequently present in the general population. Currently, surgical resection is the only curative approach for pancreatic cancer and its cystic precursors. However, only a dismal proportion of patients are eligible for surgery. Therefore, novel treatment approaches to treat pancreatic cancer and precancerous pancreatic cysts are needed. Endoscopic ultrasound (EUS)-guided ablation is an emerging minimally invasive method to treat pancreatic cancer and premalignant pancreatic cysts. Different ablative modalities have been used including alcohol, chemotherapy agents, and radiofrequency ablation. Cumulative data over the past two decades have shown that endoscopic ablation of mucinous pancreatic cysts can lead to cyst resolution in a significant proportion of the treated cysts. Furthermore, novel data are emerging about the ability to endoscopically ablate early and locally advanced pancreatic cancer. In this review, we aim to summarize the available data on the efficacy and safety of the different EUS-ablation modalities for the management of premalignant pancreatic cysts and pancreatic cancer.
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Affiliation(s)
- Alejandra Vargas
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA 23510, USA
| | - Priyata Dutta
- Department of Medicine, Trinity Health, Ann Arbor, MI 48197, USA
| | - Eileen S Carpenter
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jorge D Machicado
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
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Nakai Y. Endoscopic Ultrasound-Guided Antitumor Therapy. Gastrointest Endosc Clin N Am 2024; 34:79-89. [PMID: 37973232 DOI: 10.1016/j.giec.2023.08.004] [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] [Indexed: 11/19/2023]
Abstract
Endoscopic ultrasound (EUS) has been used for various interventions to manage intra-abdominal lesions. EUS-guided antitumor therapy via delivery of chemotherapeutic agents, energy, and radioactive seeds has advantages of less invasiveness than surgical approaches, and the anatomic proximity allows easy and accurate access to the pancreas. The feasibility of EUS-guided antitumor therapy has been reported both in pancreatic solid and cystic neoplasms, with promising preliminary results. Randomized controlled trials are mandatory to further confirm its role.
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Affiliation(s)
- Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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10
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Yoon AR, Hong J, Jung BK, Ahn HM, Zhang S, Yun CO. Oncolytic adenovirus as pancreatic cancer-targeted therapy: Where do we go from here? Cancer Lett 2023; 579:216456. [PMID: 37940067 DOI: 10.1016/j.canlet.2023.216456] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/10/2023] [Accepted: 10/17/2023] [Indexed: 11/10/2023]
Abstract
Pancreatic cancer remains one of the deadliest cancers with extremely high mortality rate, and the number of cases is expected to steadily increase with time. Pancreatic cancer is refractory to conventional cancer treatment options, like chemotherapy and radiotherapy, and commercialized immunotherapeutics, owing to its immunosuppressive and desmoplastic phenotype. Due to these reasons, development of an innovative treatment option that can overcome these challenges posed by the pancreatic tumor microenvironment (TME) is in an urgent need. The present review aims to summarize the evolution of oncolytic adenovirus (oAd) engineering and usage as therapeutics (either monotherapy or combination therapy) over the last decade to overcome these hurdles to instigate a potent antitumor effect against desmoplastic and immunosuppressive pancreatic cancer.
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Affiliation(s)
- A-Rum Yoon
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea; Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea; Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
| | - JinWoo Hong
- GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea
| | - Bo-Kyeong Jung
- GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea
| | - Hyo Min Ahn
- GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea
| | - Songnam Zhang
- Department of Medical Oncology, Yanbian University Hospital, Jilin, China
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea; Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea; Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea; GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea.
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11
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Cesur-Ergün B, Demir-Dora D. Gene therapy in cancer. J Gene Med 2023; 25:e3550. [PMID: 37354071 DOI: 10.1002/jgm.3550] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 04/28/2023] [Accepted: 05/19/2023] [Indexed: 06/26/2023] Open
Abstract
Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.
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Affiliation(s)
- Büşra Cesur-Ergün
- Faculty of Medicine, Department of Medical Pharmacology, Akdeniz University, Antalya, Turkey
- Health Sciences Institute, Department of Gene and Cell Therapy, Akdeniz University, Antalya, Turkey
| | - Devrim Demir-Dora
- Faculty of Medicine, Department of Medical Pharmacology, Akdeniz University, Antalya, Turkey
- Health Sciences Institute, Department of Gene and Cell Therapy, Akdeniz University, Antalya, Turkey
- Health Sciences Institue, Department of Medical Biotechnology, Akdeniz University, Antalya, Turkey
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12
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Varaprasad GL, Gupta VK, Prasad K, Kim E, Tej MB, Mohanty P, Verma HK, Raju GSR, Bhaskar L, Huh YS. Recent advances and future perspectives in the therapeutics of prostate cancer. Exp Hematol Oncol 2023; 12:80. [PMID: 37740236 PMCID: PMC10517568 DOI: 10.1186/s40164-023-00444-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 09/10/2023] [Indexed: 09/24/2023] Open
Abstract
Prostate cancer (PC) is one of the most common cancers in males and the fifth leading reason of death. Age, ethnicity, family history, and genetic defects are major factors that determine the aggressiveness and lethality of PC. The African population is at the highest risk of developing high-grade PC. It can be challenging to distinguish between low-risk and high-risk patients due to the slow progression of PC. Prostate-specific antigen (PSA) is a revolutionary discovery for the identification of PC. However, it has led to an increase in over diagnosis and over treatment of PC in the past few decades. Even if modifications are made to the standard PSA testing, the specificity has not been found to be significant. Our understanding of PC genetics and proteomics has improved due to advances in different fields. New serum, urine, and tissue biomarkers, such as PC antigen 3 (PCA3), have led to various new diagnostic tests, such as the prostate health index, 4K score, and PCA3. These tests significantly reduce the number of unnecessary and repeat biopsies performed. Chemotherapy, radiotherapy, and prostatectomy are standard treatment options. However, newer novel hormone therapy drugs with a better response have been identified. Androgen deprivation and hormonal therapy are evolving as new and better options for managing hormone-sensitive and castration-resistant PC. This review aimed to highlight and discuss epidemiology, various risk factors, and developments in PC diagnosis and treatment regimens.
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Affiliation(s)
- Ganji Lakshmi Varaprasad
- Department of Biological Sciences and Bioengineering, Biohybrid Systems Research Center (BSRC), Inha University, Incheon, 22212, Republic of Korea
| | - Vivek Kumar Gupta
- Department of Biological Sciences and Bioengineering, Biohybrid Systems Research Center (BSRC), Inha University, Incheon, 22212, Republic of Korea
| | - Kiran Prasad
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Eunsu Kim
- Department of Biological Sciences and Bioengineering, Biohybrid Systems Research Center (BSRC), Inha University, Incheon, 22212, Republic of Korea
| | - Mandava Bhuvan Tej
- Department of Health Care Informatics, Sacred Heart University, 5151 Park Avenue, Fair Fields, CT, 06825, USA
| | - Pratik Mohanty
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Henu Kumar Verma
- Department of Immunopathology, Institute of Lungs Health and Immunity, Helmholtz Zentrum, 85764, Neuherberg, Munich, Germany
| | - Ganji Seeta Rama Raju
- Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul, 04620, Republic of Korea.
| | - Lvks Bhaskar
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India.
| | - Yun Suk Huh
- Department of Biological Sciences and Bioengineering, Biohybrid Systems Research Center (BSRC), Inha University, Incheon, 22212, Republic of Korea.
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13
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Yue NN, Xu HM, Xu J, Zhu MZ, Zhang Y, Tian CM, Nie YQ, Yao J, Liang YJ, Li DF, Wang LS. Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives. Mol Ther Oncolytics 2023; 30:193-215. [PMID: 37663132 PMCID: PMC10471515 DOI: 10.1016/j.omto.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023] Open
Abstract
Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.
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Affiliation(s)
- Ning-ning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University), Shenzhen 518000, China
| | - Hao-ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Jing Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Min-zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong 516000, China
| | - Cheng-Mei Tian
- Department of Emergency, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
| | - Yu-qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
| | - Yu-jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen 518000, China
| | - De-feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
| | - Li-sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
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14
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Nyati S, Stricker H, Barton KN, Li P, Elshaikh M, Ali H, Brown SL, Hwang C, Peabody J, Freytag SO, Movsas B, Siddiqui F. A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent localized prostate adenocarcinoma. PLoS One 2023; 18:e0291315. [PMID: 37713401 PMCID: PMC10503775 DOI: 10.1371/journal.pone.0291315] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 08/06/2023] [Indexed: 09/17/2023] Open
Abstract
In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/mutTKSR39rep-hIL-12) was administered in 15 subjects with localized recurrent prostate cancer (T1c-T2) at increasing doses (1 × 1010, to 1 × 1012 viral particles) followed by 7-day treatment of 5-fluorocytosine (5-FC) and valganciclovir (vGCV). The primary endpoint was toxicity through day 30 while the secondary and exploratory endpoints were quantitation of IL-12, IFNγ, CXCL10 and peripheral blood mononuclear cells (PBMC). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. Total 115 adverse events were observed, most of which (92%) were grade 1/2 that did not require any treatment. Adenoviral DNA was detected only in two patients. Increase in IL-12, IFNγ, and CXCL10 was observed in 57%, 93%, and 79% patients, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts. PBMC analysis revealed immune system activation after gene therapy in cohort 5. The PSA doubling time (PSADT) pre and post treatment has a median of 1.55 years vs 1.18 years. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) was well tolerated when administered locally to prostate tumors.
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Affiliation(s)
- Shyam Nyati
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
- Department of Radiology, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, United States of America
| | - Hans Stricker
- Vattikuti Urology Institute, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Kenneth N. Barton
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Pin Li
- Department of Public Health Sciences, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Mohamed Elshaikh
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Haythem Ali
- Department of Internal Medicine, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Stephen L. Brown
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
- College of Human Medicine, Michigan State University, East Lansing, Michigan, United States of America
| | - Clara Hwang
- Department of Internal Medicine, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - James Peabody
- Vattikuti Urology Institute, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Svend O. Freytag
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
| | - Benjamin Movsas
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
- College of Human Medicine, Michigan State University, East Lansing, Michigan, United States of America
| | - Farzan Siddiqui
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, United States of America
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15
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Taylor IP, Lopez JA. Oncolytic adenoviruses and the treatment of pancreatic cancer: a review of clinical trials. J Cancer Res Clin Oncol 2023; 149:8117-8129. [PMID: 37031291 PMCID: PMC10374677 DOI: 10.1007/s00432-023-04735-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/31/2023] [Indexed: 04/10/2023]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) remains a common and difficult cancer to treat. Surgical resection and chemotherapy are standard of care and clinical outcomes remain poor. Oncolytic adenoviruses are a unique approach to the treatment of this challenging cancer, aiming to overcome the features of this disease that pose the key obstacles to standard therapies. This paper provides a detailed review of the clinical trials of conditionally-replicative adenoviruses in pancreatic cancer to date, with a brief summary of the past preclinical literature and future prospects of this therapy. METHODS MEDLINE, Embase, and clinicaltrials.gov were searched from inception to December 23rd 2022 for clinical trials of conditionally-replicative adenoviruses used in patients with pancreatic ductal adenocarcinoma. Primary features for review included patient demographics, treatment protocol including dose and administration route, adverse events, patient responses and survival rates. RESULTS The six published clinical trials suggest that objective clinical responses can be achieved with a tolerable level of side effects, even at high viral doses. The more clinically adaptable intravenous route of administration also appears to be as well tolerated as the more challenging intratumoural injections. CONCLUSION Published clinical trials provide data of the safety and some signs of oncolytic activity of conditionally-replicative adenoviruses in patients with pancreatic cancer. Importantly, on the latest trials, the easier intravenous route of administration seems to be well tolerated and safe, providing the opportunity for further clinical evaluation. It is hoped that the ongoing clinical trials will yield more promising results of this therapeutic approach against a currently intractable disease.
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Affiliation(s)
- Isobel P. Taylor
- School of Medicine and Dentistry, Griffith University, Gold Coast, Australia
| | - J. Alejandro Lopez
- School of Environment and Sciences, Griffith University, Nathan, Australia
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16
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Herpels M, Ishihara J, Sadanandam A. The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities. J Pathol 2023; 260:533-550. [PMID: 37550956 DOI: 10.1002/path.6171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 08/09/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi-faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer-associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Melanie Herpels
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Bioengineering, Imperial College London, London, UK
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, UK
| | - Anguraj Sadanandam
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Global Oncology, Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Translational Immunotherapy, Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
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17
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Dahiya DS, Chandan S, Ali H, Pinnam BSM, Gangwani MK, Al Bunni H, Canakis A, Gopakumar H, Vohra I, Bapaye J, Al-Haddad M, Sharma NR. Role of Therapeutic Endoscopic Ultrasound in Management of Pancreatic Cancer: An Endoscopic Oncologist Perspective. Cancers (Basel) 2023; 15:3235. [PMID: 37370843 DOI: 10.3390/cancers15123235] [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: 05/20/2023] [Revised: 06/08/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
Pancreatic cancer is a highly lethal disease with an aggressive clinical course. Patients with pancreatic cancer are usually asymptomatic until significant progression of their disease. Additionally, there are no effective screening guidelines for pancreatic cancer in the general population. This leads to a delay in diagnosis and treatment, resulting in poor clinical outcomes and low survival rates. Endoscopic Ultrasound (EUS) is an indispensable tool for the diagnosis and staging of pancreatic cancer. In the modern era, with exponential advancements in technology and device innovation, EUS is also being increasingly used in a variety of therapeutic interventions. In the context of pancreatic cancer where therapies are limited due to the advanced stage of the disease at diagnosis, EUS-guided interventions offer new and innovative options. Moreover, due to their minimally invasive nature and ability to provide real-time images for tumor localization and therapy, they are associated with fewer complication rates compared to conventional open and laparoscopic approaches. In this article, we detail the most current and important therapeutic applications of EUS for pancreatic cancer, namely EUS-guided Fine Needle Injections, EUS-guided Radiotherapy, and EUS-guided Ablations. Furthermore, we also discuss the feasibility and safety profile of each intervention in patients with pancreatic cancer to provide gastrointestinal medical oncologists, radiation and surgical oncologists, and therapeutic endoscopists with valuable information to facilitate patient discussions and aid in the complex decision-making process.
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Affiliation(s)
- Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, USA
| | - Saurabh Chandan
- Division of Gastroenterology and Hepatology, CHI Creighton University Medical Center, Omaha, NE 68131, USA
| | - Hassam Ali
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL 60612, USA
| | | | - Hashem Al Bunni
- Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andrew Canakis
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Harishankar Gopakumar
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Ishaan Vohra
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Jay Bapaye
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA
| | - Mohammad Al-Haddad
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Neil R Sharma
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Interventional Oncology & Surgical Endoscopy Programs (IOSE), GI Oncology Tumor Site Team, Parkview Cancer Institute, Parkview Health, Fort Wayne, IN 46845, USA
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18
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Zolaly MA, Mahallawi W, Khawaji ZY, Alahmadi MA. The Clinical Advances of Oncolytic Viruses in Cancer Immunotherapy. Cureus 2023; 15:e40742. [PMID: 37485097 PMCID: PMC10361339 DOI: 10.7759/cureus.40742] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
A promising future for oncology treatment has been brought about by the emergence of a novel approach utilizing oncolytic viruses in cancer immunotherapy. Oncolytic viruses are viruses that have been exploited genetically to assault malignant cells and activate a robust immune response. Several techniques have been developed to endow viruses with an oncolytic activity through genetic engineering. For instance, redirection capsid modification, stimulation of anti-neoplastic immune response, and genetically arming viruses with cytokines such as IL-12. Oncolytic viral clinical outcomes are sought after, particularly in more advanced cancers. The effectiveness and safety profile of the oncolytic virus in clinical studies with or without the combination of standard treatment (chemotherapy, radiotherapy, or primary excision) has been assessed using response evaluation criteria in solid tumors (RECIST). This review will comprehensively outline the most recent clinical applications and provide the results from various phases of clinical trials in a variety of cancers in the latest published literature.
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Affiliation(s)
- Mohammed A Zolaly
- Pediatric Hematology Oncology, Taibah University, Al-Madinah al-Munawwarah, SAU
| | - Waleed Mahallawi
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Taibah University, Al-Madinah al-Munawwarah, SAU
| | - Zakaria Y Khawaji
- Medicine and Surgery, Taibah University, Al-Madinah al-Munawwarah, SAU
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Lin D, Shen Y, Liang T. Oncolytic virotherapy: basic principles, recent advances and future directions. Signal Transduct Target Ther 2023; 8:156. [PMID: 37041165 PMCID: PMC10090134 DOI: 10.1038/s41392-023-01407-6] [Citation(s) in RCA: 121] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/05/2023] [Accepted: 03/14/2023] [Indexed: 04/13/2023] Open
Abstract
Oncolytic viruses (OVs) have attracted growing awareness in the twenty-first century, as they are generally considered to have direct oncolysis and cancer immune effects. With the progress in genetic engineering technology, OVs have been adopted as versatile platforms for developing novel antitumor strategies, used alone or in combination with other therapies. Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future. In this review, we summarized the basic principles of OVs in terms of their classifications, as well as the recent advances in OV-modification strategies based on their characteristics, biofunctions, and cancer hallmarks. Candidate OVs are expected to be designed as "qualified soldiers" first by improving target fidelity and safety, and then equipped with "cold weapons" for a proper cytocidal effect, "hot weapons" capable of activating cancer immunotherapy, or "auxiliary weapons" by harnessing tactics such as anti-angiogenesis, reversed metabolic reprogramming and decomposing extracellular matrix around tumors. Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects. Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.
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Affiliation(s)
- Danni Lin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, Zhejiang, China.
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
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20
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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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21
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Quillien L, Buscail L, Cordelier P. Pancreatic Cancer Cell and Gene Biotherapies: Past, Present, and Future. Hum Gene Ther 2023; 34:150-161. [PMID: 36585858 DOI: 10.1089/hum.2022.210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Solid cancers remain a major health challenge in terms of research, not only due to their structure and organization but also in the molecular and genetic variations present between tumors as well as within the same tumor. When adding on the tumor microenvironment with cancer-associated cells, vasculature, and the body's immune response (or lack of), the weapons used to tackle this disease must also be diverse and intricate. Developing gene-based therapies against tumors contributes to the diverse lines of attack already established for cancers and can potentially overcome certain obstacles encountered with these strategies, the lack of tumor selectivity with chemotherapies, for example. Given the high mortality and relapse rate associated with pancreatic cancer, novel treatments, including gene therapy, are actively being investigated. Even though no gene therapy for pancreatic cancer is currently on the market, a significant amount of clinical trials are underway, especially in active and recruiting or recently completed phases.
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Affiliation(s)
- Lorraine Quillien
- Team Therapeutic Innovation in Pancreatic Cancer, CRCT, University of Toulouse, Inserm, CNRS, University of Toulouse III-Paul Sabatier, Cancer Research Centre of Toulouse, Toulouse, France
| | - Louis Buscail
- Team Therapeutic Innovation in Pancreatic Cancer, CRCT, University of Toulouse, Inserm, CNRS, University of Toulouse III-Paul Sabatier, Cancer Research Centre of Toulouse, Toulouse, France.,Department of Gastroenterology and Pancreatology, Hôpital Rangueil, CHU de Toulouse, University Toulouse Paul Sabatier, Toulouse, France
| | - Pierre Cordelier
- Team Therapeutic Innovation in Pancreatic Cancer, CRCT, University of Toulouse, Inserm, CNRS, University of Toulouse III-Paul Sabatier, Cancer Research Centre of Toulouse, Toulouse, France
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22
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Wu T, Huang C, Yao Y, Du Z, Liu Z. Suicide Gene Delivery System Mediated by Ultrasound-Targeted Microbubble Destruction: A Promising Strategy for Cancer Therapy. Hum Gene Ther 2022; 33:1246-1259. [PMID: 36215248 DOI: 10.1089/hum.2022.152] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The treatment of malignant tumors has always been one of the challenges that have plagued researchers and clinicians. The ideal status in cancer treatment is to eliminate tumor cells while avoiding damage to normal tissues. Different approaches have been investigated to achieve such a goal, and suicide gene therapy has emerged as a novel mode of cancer treatment. This approach involves the delivery of genes encoding enzymes that activate non-toxic prodrugs into cytotoxic metabolites that cause the death of transfected cancer cells. Despite promising results obtained both in vitro and in vivo, this innovative approach has long been stalled in the clinic due to the lack of a suitable delivery system to introduce the suicide gene into cancer cells. Ultrasound-targeted microbubble destruction (UTMD) represents a valuable non-viral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents by increasing vascular and cell membrane permeability, especially in the presence of microbubbles. In this scenario, the true potential of suicide genes can be translated into clinically valuable treatments for patients. This review provides background information on suicide gene therapy and UTMD technology, summarizes the current state of knowledge about UTMD-mediated suicide gene delivery in cancer treatment, and presents an outlook on its future development.
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Affiliation(s)
- Tong Wu
- Department of Ultrasound, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Chi Huang
- Department of Ultrasound, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Yiran Yao
- Department of Ultrasound, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Zhaolin Du
- Department of Ultrasound, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Zhijun Liu
- Department of Ultrasound, Shengjing Hospital, China Medical University, Shenyang, P.R. China
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23
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Vorobjeva IV, Zhirnov OP. Modern approaches to treating cancer with oncolytic viruses. MICROBIOLOGY INDEPENDENT RESEARCH JOURNAL 2022. [DOI: 10.18527/2500-2236-2022-9-1-91-112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023] Open
Abstract
According to the World Health Organization, cancer is the second leading cause of death in the world. This serves as a powerful incentive to search for new effective cancer treatments. Development of new oncolytic viruses capable of selectively destroying cancer cells is one of the modern approaches to cancer treatment. The advantage of this method – the selective lysis of tumor cells with the help of viruses – leads to an increase in the antitumor immune response of the body, that in turn promotes the destruction of the primary tumor and its metastases. Significant progress in development of this method has been achieved in the last decade. In this review we analyze the literature data on families of oncolytic viruses that have demonstrated a positive therapeutic effect against malignant neoplasms in various localizations. We discuss the main mechanisms of the oncolytic action of viruses and assess their advantages over other methods of cancer therapy as well as the prospects for their use in clinical practice.
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Affiliation(s)
- I. V. Vorobjeva
- N. F. Gamaleya National Research Center for Epidemiology and Microbiology, D. I. Ivanovsky Institute of Virology
| | - O. P. Zhirnov
- N. F. Gamaleya National Research Center for Epidemiology and Microbiology, D. I. Ivanovsky Institute of Virology; The Russian-German Academy of Medical and Biotechnological Sciences
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24
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Oronsky B, Gastman B, Conley AP, Reid C, Caroen S, Reid T. Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot. Cancers (Basel) 2022; 14:4701. [PMID: 36230621 PMCID: PMC9562194 DOI: 10.3390/cancers14194701] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/21/2022] [Accepted: 09/25/2022] [Indexed: 11/27/2022] Open
Abstract
Oncolytic viruses, colloquially referred to as "living drugs", amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair (MMR) deficient rectal cancer, where the complete response rate was 100%, checkpoint inhibitors are not cure-alls, which suggests the need for a combination partner like oncolytic viruses to prime and augment their activity. This review focuses on adenoviruses, the most clinically investigated of all the oncolytic viruses. It covers specific design features of clinical adenoviral candidates and highlights their potential both alone and in combination with checkpoint inhibitors in clinical trials to turn immunologically "cold" and unresponsive tumors into "hotter" and more responsive ones through a domino effect. Finally, a "mix-and-match" combination of therapies based on the paradigm of the cancer-immunity cycle is proposed to augment the immune responses of oncolytic adenoviruses.
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Affiliation(s)
| | | | - Anthony P. Conley
- University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | | | - Scott Caroen
- EpicentRx, Torrey Pines, La Jolla, CA 92037, USA
| | - Tony Reid
- EpicentRx, Torrey Pines, La Jolla, CA 92037, USA
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25
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Oishi T, Ito M, Koizumi S, Horikawa M, Yamamoto T, Yamagishi S, Yamasaki T, Sameshima T, Suzuki T, Sugimura H, Namba H, Kurozumi K. Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain metastases. Mol Ther Methods Clin Dev 2022; 26:253-265. [PMID: 35892087 PMCID: PMC9307584 DOI: 10.1016/j.omtm.2022.07.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/03/2022] [Indexed: 11/29/2022]
Abstract
Lung cancer is one of the most common cancers, and the number of patients with intracranial metastases is increasing. Previously, we developed an enzyme prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system using various mesenchymal stem cells to induce apoptosis in malignant gliomas through bystander killing effects. Here, we describe stem cells from human exfoliated deciduous teeth (SHED) as gene vehicles of the TK/GCV system against a brain metastasis model of non-small cell lung cancer (NSCLC). We introduced the A168H mutant TK (TKA168H) into SHED to establish the therapeutic cells because of the latent toxicity of wild type. SHED expressing TKA168H (SHED-TK) exhibited chemotaxis to the conditioned medium of NSCLC and migrated toward implanted NSCLC in vivo. SHED-TK demonstrated a strong bystander effect in vitro and in vivo and completely eradicated H1299 NSCLC in the brain. SHED-TK cells implanted intratumorally followed by GCV administration significantly suppressed the growth of H1299 and improved survival time. These results indicate that the TKA168H variant is suitable for establishing therapeutic cells and that intratumoral injection of SHED-TK followed by GCV administration may be a useful strategy for therapeutic approaches.
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Affiliation(s)
- Tomoya Oishi
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masahiko Ito
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shinichiro Koizumi
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Makoto Horikawa
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Taisuke Yamamoto
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoru Yamagishi
- Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan.,Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomohiro Yamasaki
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tetsuro Sameshima
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroki Namba
- Department of Neurosurgery, Enshu Hospital, Hamamatsu, Japan
| | - Kazuhiko Kurozumi
- Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
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26
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Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models. Int J Mol Sci 2022; 23:ijms23168884. [PMID: 36012152 PMCID: PMC9408166 DOI: 10.3390/ijms23168884] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24–72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.
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27
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Shan X, Gong X, Li J, Wen J, Li Y, Zhang Z. Current approaches of nanomedicines in the market and various stage of clinical translation. Acta Pharm Sin B 2022; 12:3028-3048. [PMID: 35865096 PMCID: PMC9293719 DOI: 10.1016/j.apsb.2022.02.025] [Citation(s) in RCA: 138] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/16/2021] [Accepted: 02/21/2022] [Indexed: 12/11/2022] Open
Abstract
Compared with traditional drug therapy, nanomedicines exhibit intriguing biological features to increase therapeutic efficiency, reduce toxicity and achieve targeting delivery. This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials, which manifests a diversified trend in carrier types, applied indications and mechanisms of action. From the perspective of indications, this article presents an overview of the applications of nanomedicines involving the prevention, diagnosis and treatment of various diseases, which include cancer, infections, blood disorders, cardiovascular diseases, immuno-associated diseases and nervous system diseases, etc. Moreover, the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.
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Affiliation(s)
- Xiaoting Shan
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiang Gong
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jie Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
| | - Jingyuan Wen
- School of Pharmacy, University of Auckland, Auckland 1142, New Zealand
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhiwen Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
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28
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Nisar M, Paracha RZ, Adil S, Qureshi SN, Janjua HA. An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer. Front Oncol 2022; 12:875188. [PMID: 35686109 PMCID: PMC9171400 DOI: 10.3389/fonc.2022.875188] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy resistance and peculiar tumor microenvironment, which diminish or mitigate the effects of therapies, make pancreatic cancer one of the deadliest malignancies to manage and treat. Advanced immunotherapies are under consideration intending to ameliorate the overall patient survival rate in pancreatic cancer. Oncolytic viruses therapy is a new type of immunotherapy in which a virus after infecting and lysis the cancer cell induces/activates patients’ immune response by releasing tumor antigen in the blood. The current review covers the pathways and molecular ablation that take place in pancreatic cancer cells. It also unfolds the extensive preclinical and clinical trial studies of oncolytic viruses performed and/or undergoing to design an efficacious therapy against pancreatic cancer.
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Affiliation(s)
- Maryum Nisar
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Rehan Zafar Paracha
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Sidra Adil
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | | | - Hussnain Ahmed Janjua
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad, Pakistan
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29
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Kaur J, Jaruvongvanich V, Chandrasekhara V. Endoscopic ultrasound-guided injectable therapy for pancreatic cancer: A systematic review. World J Gastroenterol 2022; 28:2383-2395. [PMID: 35800184 PMCID: PMC9185216 DOI: 10.3748/wjg.v28.i21.2383] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/18/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Given the low survival rate in pancreatic cancer, new therapeutic techniques have been explored, especially for unresectable or borderline resectable disease. Endoscopic ultrasound (EUS) provides real-time imaging and minimally invasive access for local and targeted injection of anti-tumor agents directly into the pancreatic tumor. Limited studies have been reported using this technique for the treatment of pancreatic ductal adenocarcinoma (PDAC).
AIM To evaluate the progress made with EUS-guided injectable therapies in the treatment of PDAC.
METHODS All original articles published in English until July 15, 2021, were retrieved via a library-assisted literature search from Ovid Evidence-Based Medicine Reviews and Scopus databases. Reference lists were reviewed to identify additional relevant articles. Prospective clinical studies evaluating the use of EUS-guided injectable therapies in PDAC were included. Studies primarily directed at non-EUS injectable therapies and other malignancies were excluded. Retrieved manuscripts were reviewed descriptively with on critical appraisal of published studies based on their methods and outcome measures such as safety, feasibility, and effectiveness in terms of tumor response and survival. Heterogeneity in data outcomes and therapeutic techniques limited the ability to perform comparative statistical analysis.
RESULTS A total of thirteen articles (503 patients) were found eligible for inclusion. The EUS-injectable therapies used were heterogeneous among the studies consisting of immunotherapy (n = 5) in 59 patients, chemotherapy (n = 1) in 36 patients, and viral and other biological therapies (n = 7) in 408 patients. Eleven of the studies reviewed were single armed while two were double armed with one randomized trial and one non-randomized comparative study. Overall, the included studies demonstrated EUS-guided injectable therapies to be safe and feasible with different agents as monotherapy or in conjunction with other modalities. Promising results were also observed regarding their efficacy and survival parameters in patients with PDAC.
CONCLUSION EUS-guided injectable therapies, including immunotherapy, chemotherapy, and viral or other biological therapies have shown minimal adverse events and potential efficacy in the treatment of PDAC. Comparative studies, including controlled trials, are required to confirm these results in order to offer novel EUS-based treatment options for patients with PDAC.
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Affiliation(s)
- Jyotroop Kaur
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | | | - Vinay Chandrasekhara
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
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30
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Papaefthymiou A, Doukatas A, Galanopoulos M. Pancreatic cancer and oligonucleotide therapy: Exploring novel therapeutic options and targeting chemoresistance. Clin Res Hepatol Gastroenterol 2022; 46:101911. [PMID: 35346893 DOI: 10.1016/j.clinre.2022.101911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/15/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023]
Abstract
Pancreatic cancer (PC) represents a malignancy with increased mortality rate, as less than 10% of patients survive for 5 years after diagnosis. Current evolution in basic sciences has revealed promising results by decrypting genetic loci vulnerable to mutations, as potential targets of novel treatment choices. In this regard, the "Oligonucleotide therapeutics", based on synthetic nucleotides, modify the function and expression of their targets. Antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNAs (miRNAs), aptamers, CpG oligodeoxynucleotides and decoys comprise the main representatives of this emerging technology, by regulating oncogenes' expression, restoring DNA repairment mechanisms, sensitizing cancer cells in chemotherapy, and inhibiting PC progress. A plethora of genetic treatment molecules and respective targets have been described and are currently studied, thus providing a broad range of probable pharmaceutical options. This narrative review illuminates the main parameters of genetic treatment molecules for PC and underlines their deficiencies, to clarify the upcoming future and trigger further investigation in PC management.
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Affiliation(s)
- Apostolis Papaefthymiou
- Department of Gastroenterology, University Hospital of Larissa, Larissa, 41110, Thessaly, Greece.
| | - Aris Doukatas
- Department of Pharmacy, National and Kapodistrian University of Athens, Attiki, Greece
| | - Michail Galanopoulos
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
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31
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Cordeiro RA, Mendonça PV, Coelho J, Faneca H. Engineering silica-polymer hybrid nanosystems for dual drug and gene delivery. BIOMATERIALS ADVANCES 2022; 135:212742. [PMID: 35929215 DOI: 10.1016/j.bioadv.2022.212742] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/23/2022] [Accepted: 02/27/2022] [Indexed: 06/15/2023]
Abstract
In recent years, it has been shown that a combination of different antitumour strategies involving distinct therapeutic agents, such as chemical compounds and genetic material, could result in an effective therapeutic activity that is much higher than that obtained by conventionally used individual approaches. Therefore, the main goal of this work was to develop a new hybrid nanosystem based on mesoporous silica nanoparticles and polymers to efficiently transport and deliver drug and plasmid DNA into cancer cells. Moreover, its potential to mediate a combinatorial antitumour strategy involving epirubicin and herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy was evaluated. For this purpose, various cationic polymers were assessed, including poly(β-amino ester) homopolymer, gelatine type A, gelatine type B, and poly(ethylene glycol)-b-poly(2-aminoethyl methacrylate hydrochloride) block copolymer. The obtained results show that using different polymers leads to nanosystems with different physicochemical properties and, consequently, different biological activities. The best formulation was obtained for hybrid nanosystems coated with PEG-b-PAMA. They demonstrated the ability to cotransport and codeliver an anticancer drug and plasmid DNA and effectively mediate the combined antitumour strategy in 2D and 3D tumour cell culture models. In summary, we developed a novel silica- and polymer-based nanosystem able to mediate a dual chemotherapeutic and suicide gene therapy strategy with a much higher therapeutic effect than that obtained through the use of individual approaches, showing its potential for cancer treatment.
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Affiliation(s)
- Rosemeyre A Cordeiro
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Patrícia V Mendonça
- University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Department of Chemical Engineering, Rua Sílvio Lima-Polo II, 3030-790 Coimbra, Portugal
| | - Jorge Coelho
- University of Coimbra, Centre for Mechanical Engineering, Materials and Processes, Department of Chemical Engineering, Rua Sílvio Lima-Polo II, 3030-790 Coimbra, Portugal
| | - Henrique Faneca
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal.
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32
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Jawalagatti V, Kirthika P, Hewawaduge C, Park JY, Yang MS, Oh B, So MY, Kim B, Lee JH. A Simplified SARS-CoV-2 Mouse Model Demonstrates Protection by an Oral Replicon-Based mRNA Vaccine. Front Immunol 2022; 13:811802. [PMID: 35250985 PMCID: PMC8888445 DOI: 10.3389/fimmu.2022.811802] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/25/2022] [Indexed: 12/24/2022] Open
Abstract
A mouse model of SARS-CoV-2 that can be developed in any molecular biology lab with standard facilities will be valuable in evaluating drugs and vaccines. Here we present a simplified SARS-CoV-2 mouse model exploiting the rapid adenoviral purification method. Mice that are sensitive to SARS-CoV-2 infection were generated by transducing human angiotensin-converting enzyme 2 (hACE2) by an adenovirus. The expression kinetics of the hACE2 in transduced mice were assessed by immunohistochemistry, RT-PCR, and qPCR. Further, the ability of the hACE2 to support viral replication was determined in vitro and in vivo. The hACE2 expression in the lungs of mice was observed for at least nine days after transduction. The murine macrophages expressing hACE2 supported viral replication with detection of high viral titers. Next, in vivo studies were carried out to determine viral replication and lung disease following SARS-CoV-2 challenge. The model supported viral replication, and the challenged mouse developed lung disease characteristic of moderate interstitial pneumonia. Further, we illustrated the utility of the system by demonstrating protection using an oral mRNA vaccine. The multicistronic vaccine design enabled by the viral self-cleaving peptides targets receptor binding domain (RBD), heptad repeat domain (HR), membrane glycoprotein (M) and epitopes of nsp13 of parental SARS-CoV-2. Further, Salmonella and Semliki Forest virus replicon were exploited, respectively, for gene delivery and mRNA expression. We recorded potent cross-protective neutralizing antibodies in immunized mice against the SARS-CoV-2 delta variant. The vaccine protected the mice against viral replication and SARS-CoV-2-induced weight loss and lung pathology. The findings support the suitability of the model for preclinical evaluation of anti-SARS-CoV-2 therapies and vaccines. In addition, the findings provide novel insights into mRNA vaccine design against infectious diseases not limiting to SARS-CoV-2.
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Affiliation(s)
- Vijayakumar Jawalagatti
- Department of Veterinary Public Health, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Perumalraja Kirthika
- Department of Veterinary Public Health, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Chamith Hewawaduge
- Department of Veterinary Public Health, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Ji-Young Park
- Department of Veterinary Public Health, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Myeon-Sik Yang
- Department of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Byungkwan Oh
- Department of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Mi Young So
- Department of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - Bumseok Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
| | - John Hwa Lee
- Department of Veterinary Public Health, College of Veterinary Medicine, Jeonbuk National University, Iksan, South Korea
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33
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Sbeit W, Napoléon B, Khoury T. Endoscopic ultrasound role in pancreatic adenocarcinoma treatment: A review focusing on technical success, safety and efficacy. World J Gastroenterol 2022; 28:332-347. [PMID: 35110953 PMCID: PMC8771609 DOI: 10.3748/wjg.v28.i3.332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/22/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
The impressive technological advances in recent years have rapidly translated into the shift of endoscopic ultrasound (EUS) from diagnostic modality into an interventional and therapeutic tool. Despite the great advance in its diagnosis, the majority of pancreatic adenocarcinoma cases are inoperable when diagnosed, thus demanding alternative optional therapies. EUS has emerged as an easy, minimally invasive modality targeting this carcinoma with different interventions that have been reported recently. In this review we summarize the evolving role of interventional therapeutic EUS in pancreatic adenocarcinoma management.
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Affiliation(s)
- Wisam Sbeit
- Department of Gastroenterology, Galilee Medical Center, Faculty of Medicine in the Galilee, Bar-Ilan University, Nahariya 2221006, Israel
| | - Bertrand Napoléon
- Department of Endoscopy Unit, Private Hospital Jean Mermoz, Ramsay Generale de Sante, Lyon 69008, France
| | - Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Faculty of Medicine in the Galilee, Bar-Ilan University, Nahariya 2221006, Israel
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34
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Bratanic A, Bozic D, Mestrovic A, Martinovic D, Kumric M, Ticinovic Kurir T, Bozic J. Role of endoscopic ultrasound in anticancer therapy: Current evidence and future perspectives. World J Gastrointest Oncol 2021; 13:1863-1879. [PMID: 35070030 PMCID: PMC8713319 DOI: 10.4251/wjgo.v13.i12.1863] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/17/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
The digestive system is one of the most common sites of malignancies in humans. Since gastrointestinal tumors represent a massive global health burden both in terms of morbidity and health care expenditures, scientists continuously develop novel diagnostic and therapeutic methods to ameliorate the detrimental effects of this group of diseases. Apart from the well-established role of the endoscopic ultrasound (EUS) in the diagnostic course of gastrointestinal and hepatobiliary malignancies, we have recently become acquainted with a vast array of its therapeutic possibilities. A multitude of previously established, evidence-based methods that might now be guided by the EUS emerged: Radiofrequency ablation, brachytherapy, fine needle injection, celiac plexus neurolysis, and endoscopic submucosal dissection. In this review we endeavored to provide a comprehensive overview of the role of these methods in different malignancies of the digestive system, primarily in the treatment and symptom control in pancreatic cancer, and additionally in the management of hepatic, gastrointestinal tumors, and pancreatic cysts.
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Affiliation(s)
- Andre Bratanic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Dorotea Bozic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Antonio Mestrovic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Dinko Martinovic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Tina Ticinovic Kurir
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Department of Endocrinology, University Hospital of Split, Split 21000, Croatia
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
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35
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Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, Li Z, Pan CX. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol 2021; 14:156. [PMID: 34579759 PMCID: PMC8475356 DOI: 10.1186/s13045-021-01164-5] [Citation(s) in RCA: 342] [Impact Index Per Article: 85.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022] Open
Abstract
Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.
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Affiliation(s)
- Shaoming Zhu
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,Department of Urology, Beijing Chao-Yang Hospital, Beijing, China
| | - Tian Zhang
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, DUMC 103861, Durham, NC, 27710, USA
| | - Lei Zheng
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Hongtao Liu
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,University of Chicago, Chicago, IL, USA
| | - Wenru Song
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,Kira Pharmaceuticals, Cambridge, MA, USA
| | - Delong Liu
- Chinese American Hematologist and Oncologist Network, New York, NY, USA.,New York Medical College, Valhalla, NY, USA
| | - Zihai Li
- Chinese American Hematologist and Oncologist Network, New York, NY, USA. .,Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, USA.
| | - Chong-Xian Pan
- Chinese American Hematologist and Oncologist Network, New York, NY, USA. .,Harvard Medical School, West Roxbury, MA, 02132, USA.
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36
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Xue J, Chen K, Hu H, Gopinath SCB. Progress in gene therapy treatments for prostate cancer. Biotechnol Appl Biochem 2021; 69:1166-1175. [PMID: 33988271 DOI: 10.1002/bab.2193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 05/12/2021] [Indexed: 01/17/2023]
Abstract
Prostate cancer is one of the predominant cancers affecting men and has been widely reported. In the past, various therapies and drugs have been proposed to treat prostate cancer. Among these treatments, gene therapy has been considered to be an optimal and widely applicable treatment. Furthermore, due to the increased specificity of gene sequence complementation, the targeted delivery of complementary gene sequences may represent a useful treatment in certain instances. Various gene therapies, including tumor-suppressor gene therapy, suicide gene therapy, immunomodulation gene therapy and anti-oncogene therapies, have been established to treat a wide range of diseases, such as cardiac disease, cystic fibrosis, HIV/AIDS, diabetes, hemophilia, and cancers. To this end, several gene therapy clinical trials at various phases are underway. This overview describes the developments and progress in gene therapy, with a special focus being placed on prostate cancer.
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Affiliation(s)
- Jingxin Xue
- Department of Urology, Affiliated Jinan Third Hospital of Jining Medical University, Jining Medical University, Jinan, Shandong, China
| | - Keming Chen
- Department of Urology, Affiliated Jinan Third Hospital of Jining Medical University, Jining Medical University, Jinan, Shandong, China
| | - Heyi Hu
- Department of Urology, Affiliated Jinan Third Hospital of Jining Medical University, Jining Medical University, Jinan, Shandong, China
| | - Subash C B Gopinath
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar, Perlis, 01000, Malaysia.,Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, Perlis, 02600, Malaysia
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Mozaffari Nejad AS, Noor T, Munim ZH, Alikhani MY, Ghaemi A. A bibliometric review of oncolytic virus research as a novel approach for cancer therapy. Virol J 2021; 18:98. [PMID: 33980264 PMCID: PMC8113799 DOI: 10.1186/s12985-021-01571-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Background In recent years, oncolytic viruses (OVs) have drawn attention as a novel therapy to various types of cancers, both in clinical and preclinical cancer studies all around the world. Consequently, researchers have been actively working on enhancing cancer therapy since the early twentieth century. This study presents a systematic review of the literature on OVs, discusses underlying research clusters and, presents future directions of OVs research. Methods A total of 1626 published articles related to OVs as cancer therapy were obtained from the Web of Science (WoS) database published between January 2000 and March 2020. Various aspects of OVs research, including the countries/territories, institutions, journals, authors, citations, research areas, and content analysis to find trending and emerging topics, were analysed using the bibliometrix package in the R-software. Results In terms of the number of publications, the USA based researchers were the most productive (n = 611) followed by Chinese (n = 197), and Canadian (n = 153) researchers. The Molecular Therapy journal ranked first both in terms of the number of publications (n = 133) and local citations (n = 1384). The most prominent institution was Mayo Clinic from the USA (n = 117) followed by the University of Ottawa from Canada (n = 72), and the University of Helsinki from Finland (n = 63). The most impactful author was Bell J.C with the highest number of articles (n = 67) and total local citations (n = 885). The most impactful article was published in the Cell journal. In addition, the latest OVs research mainly builds on four research clusters. Conclusion The domain of OVs research has increased at a rapid rate from 2000 to 2020. Based on the synthesis of reviewed studies, adenovirus, herpes simplex virus, reovirus, and Newcastle disease virus have shown potent anti-cancer activity. Developed countries such as the USA, Canada, the UK, and Finland were the most productive, hence, contributed most to this field. Further collaboration will help improve the clinical research translation of this therapy and bring benefits to cancer patients worldwide.
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Affiliation(s)
| | - Tehjeeb Noor
- Faculty of Medicine, University of Bergen, Horten, Norway
| | - Ziaul Haque Munim
- Faculty of Technology, Natural and Maritime Sciences, University of South-Eastern Norway, Horten, Norway
| | - Mohammad Yousef Alikhani
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Amir Ghaemi
- Department of Influenza and Other Respiratory Viruses, Pasteur Institute of Iran, Tehran, Iran.
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Antonova DV, Zinovyeva MV, Kondratyeva LG, Sass AV, Alekseenko IV, Pleshkan VV. Possibility for Transcriptional Targeting of Cancer-Associated Fibroblasts-Limitations and Opportunities. Int J Mol Sci 2021; 22:ijms22073298. [PMID: 33804861 PMCID: PMC8038081 DOI: 10.3390/ijms22073298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 12/27/2022] Open
Abstract
Cancer-associated fibroblasts (CAF) are attractive therapeutic targets in the tumor microenvironment. The possibility of using CAFs as a source of therapeutic molecules is a challenging approach in gene therapy. This requires transcriptional targeting of transgene expression by cis-regulatory elements (CRE). Little is known about which CREs can provide selective transgene expression in CAFs. We hypothesized that the promoters of FAP, CXCL12, IGFBP2, CTGF, JAG1, SNAI1, and SPARC genes, the expression of whose is increased in CAFs, could be used for transcriptional targeting. Analysis of the transcription of the corresponding genes revealed that unique transcription in model CAFs was characteristic for the CXCL12 and FAP genes. However, none of the promoters in luciferase reporter constructs show selective activity in these fibroblasts. The CTGF, IGFBP2, JAG1, and SPARC promoters can provide higher transgene expression in fibroblasts than in cancer cells, but the nonspecific viral promoters CMV, SV40, and the recently studied universal PCNA promoter have the same features. The patterns of changes in activity of various promoters relative to each other observed for human cell lines were similar to the patterns of activity for the same promoters both in vivo and in vitro in mouse models. Our results reveal restrictions and features for CAF transcriptional targeting.
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Affiliation(s)
- Dina V. Antonova
- Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia; (D.V.A.); (M.V.Z.); (L.G.K.); (A.V.S.); (I.V.A.)
| | - Marina V. Zinovyeva
- Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia; (D.V.A.); (M.V.Z.); (L.G.K.); (A.V.S.); (I.V.A.)
| | - Liya G. Kondratyeva
- Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia; (D.V.A.); (M.V.Z.); (L.G.K.); (A.V.S.); (I.V.A.)
| | - Alexander V. Sass
- Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia; (D.V.A.); (M.V.Z.); (L.G.K.); (A.V.S.); (I.V.A.)
| | - Irina V. Alekseenko
- Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia; (D.V.A.); (M.V.Z.); (L.G.K.); (A.V.S.); (I.V.A.)
- Gene Oncotherapy Sector, Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia
- Institute of Oncogynecology and Mammology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Victor V. Pleshkan
- Department of Genomics and Postgenomic Technologies, Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia; (D.V.A.); (M.V.Z.); (L.G.K.); (A.V.S.); (I.V.A.)
- Gene Oncotherapy Sector, Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia
- Correspondence:
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Holbrook MC, Goad DW, Grdzelishvili VZ. Expanding the Spectrum of Pancreatic Cancers Responsive to Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Challenges and Solutions. Cancers (Basel) 2021; 13:1171. [PMID: 33803211 PMCID: PMC7963195 DOI: 10.3390/cancers13051171] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/05/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis and a dismal survival rate, expected to become the second leading cause of cancer-related deaths in the United States. Oncolytic virus (OV) is an anticancer approach that utilizes replication-competent viruses to preferentially infect and kill tumor cells. Vesicular stomatitis virus (VSV), one such OV, is already in several phase I clinical trials against different malignancies. VSV-based recombinant viruses are effective OVs against a majority of tested PDAC cell lines. However, some PDAC cell lines are resistant to VSV. Upregulated type I IFN signaling and constitutive expression of a subset of interferon-simulated genes (ISGs) play a major role in such resistance, while other mechanisms, such as inefficient viral attachment and resistance to VSV-mediated apoptosis, also play a role in some PDACs. Several alternative approaches have been shown to break the resistance of PDACs to VSV without compromising VSV oncoselectivity, including (i) combinations of VSV with JAK1/2 inhibitors (such as ruxolitinib); (ii) triple combinations of VSV with ruxolitinib and polycations improving both VSV replication and attachment; (iii) combinations of VSV with chemotherapeutic drugs (such as paclitaxel) arresting cells in the G2/M phase; (iv) arming VSV with p53 transgenes; (v) directed evolution approach producing more effective OVs. The latter study demonstrated impressive long-term genomic stability of complex VSV recombinants encoding large transgenes, supporting further clinical development of VSV as safe therapeutics for PDAC.
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Affiliation(s)
| | | | - Valery Z. Grdzelishvili
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA; (M.C.H.); (D.W.G.)
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Barton KN, Siddiqui F, Pompa R, Freytag SO, Khan G, Dobrosotskaya I, Ajlouni M, Zhang Y, Cheng J, Movsas B, Kwon D. Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer. MOLECULAR THERAPY-ONCOLYTICS 2020; 20:94-104. [PMID: 33575474 PMCID: PMC7851493 DOI: 10.1016/j.omto.2020.11.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/24/2020] [Indexed: 12/11/2022]
Abstract
The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 1011, 3 × 1011, or 1 × 1012 viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL12, interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/mutTKSR39rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39rep-hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5–20.0) months. The study maximum tolerated dose (MTD) was not reached.
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Affiliation(s)
- Kenneth N Barton
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Farzan Siddiqui
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Robert Pompa
- Department of Gastroenterology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Svend O Freytag
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Gazala Khan
- Department of Oncology Hematology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Irina Dobrosotskaya
- Department of Oncology Hematology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Munther Ajlouni
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Yingshu Zhang
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Jingfang Cheng
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Benjamin Movsas
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - David Kwon
- Division of Surgical Oncology, Department of Surgery, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
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Zhang B, Cheng P. Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol Cancer 2020; 19:158. [PMID: 33172438 PMCID: PMC7656670 DOI: 10.1186/s12943-020-01275-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
As a promising therapeutic strategy, oncolytic virotherapy has shown potent anticancer efficacy in numerous pre-clinical and clinical trials. Oncolytic viruses have the capacity for conditional-replication within carcinoma cells leading to cell death via multiple mechanisms, including direct lysis of neoplasms, induction of immunogenic cell death, and elicitation of innate and adaptive immunity. In addition, these viruses can be engineered to express cytokines or chemokines to alter tumor microenvironments. Combination of oncolytic virotherapy with other antitumor therapeutic modalities, such as chemotherapy and radiation therapy as well as cancer immunotherapy can be used to target a wider range of tumors and promote therapeutic efficacy. In this review, we outline the basic biological characteristics of oncolytic viruses and the underlying mechanisms that support their use as promising antitumor drugs. We also describe the enhanced efficacy attributed to virotherapy combined with other drugs for the treatment of cancer.
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Affiliation(s)
- Bin Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu, 610041, PR China
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu, 610041, PR China.
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Nakai Y, Chang KJ. EUS-guided fine-needle injection for pancreatic cancer: back to the future. Gastrointest Endosc 2020; 92:1053-1054. [PMID: 33160487 DOI: 10.1016/j.gie.2020.06.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Yousuke Nakai
- Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenneth J Chang
- Division of Gastroenterology and Hepatology, H. H. Chao Comprehensive Digestive Disease Center, University of California, Irvine Medical Center, Orange, California, USA
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Tassone E, Muscolini M, van Montfoort N, Hiscott J. Oncolytic virotherapy for pancreatic ductal adenocarcinoma: A glimmer of hope after years of disappointment? Cytokine Growth Factor Rev 2020; 56:141-148. [PMID: 32859494 DOI: 10.1016/j.cytogfr.2020.07.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and highly lethal malignancies. Existing therapeutic interventions have so far been unsuccessful in improving prognosis, and survival remains very poor. Oncolytic virotherapy represents a promising, yet not fully explored, alternative strategy for the treatment of PDAC. Oncolytic viruses (OVs) infect, replicate within and lyse tumor cells specifically and stimulate antitumor immune responses. Multiple challenges have hampered the efficacy of oncolytic virotherapy for PDAC, the most significant being the desmoplastic and immunosuppressive pancreatic tumor microenvironment (TME). The TME limits the access of therapeutic drugs and the infiltration of effector T cells and natural killer (NK) cells into the tumor mass. Additionally, cancer cells promote the secretion of immunosuppressive factors and develop mechanisms to evade the host immune system. Because of their oncolytic and immune-stimulating properties, OVs are the ideal candidates for counteracting the pancreatic immunosuppressive TME and for designing combination therapies that can be clinically exploited in clinical trials that seek to improve the prognosis of PDAC.
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Affiliation(s)
- Evelyne Tassone
- Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy.
| | | | - Nadine van Montfoort
- Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - John Hiscott
- Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
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