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Hsu CY, Pallathadka H, Jasim SA, Rizaev J, Olegovich Bokov D, Hjazi A, Mahajan S, Mustafa YF, Husseen B, Jawad MA. Innovations in cancer immunotherapy: A comprehensive overview of recent breakthroughs and future directions. Crit Rev Oncol Hematol 2025; 206:104588. [PMID: 39667718 DOI: 10.1016/j.critrevonc.2024.104588] [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: 11/07/2024] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024] Open
Abstract
A major advance in cancer treatment has been the development and refinement of cancer immunotherapy. The discovery of immunotherapies for a wide range of cancers has revolutionized cancer treatment paradigms. Despite relapse or refractory disease, immunotherapy approaches can prolong the life expectancy of metastatic cancer patients. Multiple therapeutic approaches and agents are currently being developed to manipulate various aspects of the immune system. Oncolytic viruses, cancer vaccines, adoptive cell therapies, monoclonal antibodies, cytokine therapies, and inhibitors of immune checkpoints have all proven successful in clinical trials. There are several types of immunotherapeutic approaches available for treating cancer, and others are being tested in preclinical and clinical settings. Immunotherapy has proven successful, and many agents and strategies have been developed to improve its effectiveness. The purpose of this article is to present a comprehensive overview of current immunotherapy approaches used to treat cancer. Cancer immunotherapy advancements, emerging patterns, constraints, and potential future breakthroughs are also discussed.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, AZ 85004, USA
| | | | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques department, College of Health and medical technology, University of Al-maarif, Anbar, Iraq.
| | - Jasur Rizaev
- Department of Public health and Healthcare management, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy named after A.P. Nelyubin, Sechenov First Moscow State Medical University, Russia; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Shriya Mahajan
- Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab 140417, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Beneen Husseen
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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Kar S, Mehrotra S, Prajapati VK. From infection to remedy: Harnessing oncolytic viruses in cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:213-257. [PMID: 39978967 DOI: 10.1016/bs.apcsb.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.
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Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Kiaheyrati N, Babaei A, Ranji R, Bahadoran E, Taheri S, Farokhpour Z. Cancer therapy with the viral and bacterial pathogens: The past enemies can be considered the present allies. Life Sci 2024; 349:122734. [PMID: 38788973 DOI: 10.1016/j.lfs.2024.122734] [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: 03/02/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024]
Abstract
Cancer continues to be one of the leading causes of mortality worldwide despite significant advancements in cancer treatment. Many difficulties have arisen as a result of the detrimental consequences of chemotherapy and radiotherapy as a common cancer therapy, such as drug inability to penetrate deep tumor tissue, and also the drug resistance in tumor cells continues to be a major concern. These obstacles have increased the need for the development of new techniques that are more selective and effective against cancer cells. Bacterial-based therapies and the use of oncolytic viruses can suppress cancer in comparison to other cancer medications. The tumor microenvironment is susceptible to bacterial accumulation and proliferation, which can trigger immune responses against the tumor. Oncolytic viruses (OVs) have also gained considerable attention in recent years because of their potential capability to selectively target and induce apoptosis in cancer cells. This review aims to provide a comprehensive summary of the latest literature on the role of bacteria and viruses in cancer treatment, discusses the limitations and challenges, outlines various strategies, summarizes recent preclinical and clinical trials, and emphasizes the importance of optimizing current strategies for better clinical outcomes.
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Affiliation(s)
- Niloofar Kiaheyrati
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Abouzar Babaei
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran.
| | - Reza Ranji
- Department of Genetics, Faculty of Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ensiyeh Bahadoran
- School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Shiva Taheri
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Farokhpour
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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Suzuki T, Uchida H. Induction of necroptosis in multinucleated giant cells induced by conditionally replicating syncytial oHSV in co-cultures of cancer cells and non-cancerous cells. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200803. [PMID: 38706990 PMCID: PMC11067338 DOI: 10.1016/j.omton.2024.200803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 04/11/2024] [Indexed: 05/07/2024]
Abstract
Viral modifications enabling syncytium formation in infected cells can augment lysis by oncolytic herpes simplex viruses (oHSVs) which selectively kill cancer cells. In the case of receptor-retargeted oHSVs (RR-oHSVs) that exclusively enter and spread to cancer cells, anti-tumor effects can be enhanced in a magnitude of >100,000-fold by modifying the virus to a syncytial type (RRsyn-oHSV). However, when syncytia containing non-cancerous cells are induced by conditionally replicating syncytial oHSV (CRsyn-oHSV), syncytial death occurs at an early stage. This results in limited anti-tumor effects of the CRsyn-oHSV. Here, we investigated whether necroptosis is involved in death of the syncytia formed by the fusion of cancer cells and non-cancerous cells. Mixed-lineage kinase domain-like (MLKL), a molecule executing necroptosis, was expressed in all murine cancer cell lines examined, while receptor-interacting protein kinase 3 (RIPK3), which phosphorylates MLKL, was absent from most cell lines. In contrast, RIPK3 was expressed in non-cancerous murine fibroblast cell lines. When a CRsyn-oHSV-infected RIPK3-deficient cancer cell line was co-cultured with the fibroblast cell line, but not with the cancer cells themselves, MLKL was phosphorylated and syncytial death was induced. These results indicate that early necroptosis is induced in multinucleated giant cells formed by CRsyn-oHSV when they also contain non-cancerous cells.
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Affiliation(s)
- Takuma Suzuki
- Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
- Project Division of Cancer Biomolecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Hiroaki Uchida
- Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
- Project Division of Cancer Biomolecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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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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Sibal PA, Matsumura S, Ichinose T, Bustos‐Villalobos I, Morimoto D, Eissa IR, Abdelmoneim M, Aboalela MAM, Mukoyama N, Tanaka M, Naoe Y, Kasuya H. STING activator 2'3'-cGAMP enhanced HSV-1-based oncolytic viral therapy. Mol Oncol 2024; 18:1259-1277. [PMID: 38400597 PMCID: PMC11076993 DOI: 10.1002/1878-0261.13603] [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: 10/12/2023] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
Oncolytic viruses (OVs) can selectively replicate in tumor cells and remodel the microenvironment of immunologically cold tumors, making them a promising strategy to evoke antitumor immunity. Similarly, agonists of the stimulator of interferon genes (STING)-interferon (IFN) pathway, the main cellular antiviral system, provide antitumor benefits by inducing the activation of dendritic cells (DC). Considering how the activation of the STING-IFN pathway could potentially inhibit OV replication, the use of STING agonists alongside OV therapy remains largely unexplored. Here, we explored the antitumor efficacy of combining an HSV-1-based OV, C-REV, with a membrane-impermeable STING agonist, 2'3'-GAMP. Our results demonstrated that tumor cells harbor a largely defective STING-IFN pathway, thereby preventing significant antiviral IFN induction regardless of the permeability of the STING agonist. In vivo, the combination therapy induced more proliferative KLRG1-high PD1-low CD8+ T-cells and activated CD103+ DC in the tumor site and increased tumor-specific CD44+ CD8+ T-cells in the lymph node. Overall, the combination therapy of C-REV with 2'3'-cGAMP elicited antitumor immune memory responses and significantly enhanced systemic antitumor immunity in both treated and non-treated distal tumors.
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Affiliation(s)
- Patricia Angela Sibal
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
- Department of Surgery II, Graduate School of MedicineNagoya UniversityJapan
| | - Shigeru Matsumura
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
| | - Toru Ichinose
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
| | | | - Daishi Morimoto
- Department of Surgery II, Graduate School of MedicineNagoya UniversityJapan
| | - Ibrahim R. Eissa
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
- Department of Surgery II, Graduate School of MedicineNagoya UniversityJapan
- Faculty of ScienceTanta UniversityEgypt
| | - Mohamed Abdelmoneim
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
- Department of Surgery II, Graduate School of MedicineNagoya UniversityJapan
- Department of Microbiology, Faculty of Veterinary MedicineZagazig UniversityEgypt
| | - Mona Alhussein Mostafa Aboalela
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
- Department of Surgery II, Graduate School of MedicineNagoya UniversityJapan
- Medical Microbiology and Immunology Department, Faculty of MedicineZagazig UniversityEgypt
| | - Nobuaki Mukoyama
- Department of Otolaryngology Graduate School of MedicineNagoya UniversityJapan
| | | | - Yoshinori Naoe
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
| | - Hideki Kasuya
- Cancer Immune Therapy Research Center, Graduate School of MedicineNagoya UniversityJapan
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Dabiri R, Rashid MU, Khan OS, Jehanzeb S, Alomari M, Zafar H, Zahid E, Rahman AU, Karam A, Ahmad S. Immune modulators for pancreatic ductal adenocarcinoma therapy. IMMUNE LANDSCAPE OF PANCREATIC CANCER DEVELOPMENT AND DRUG RESISTANCE 2024:103-129. [DOI: 10.1016/b978-0-443-23523-8.00021-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Li Y, Duan HY, Yang KD, Ye JF. Advancements and challenges in oncolytic virus therapy for gastrointestinal tumors. Biomed Pharmacother 2023; 168:115627. [PMID: 37812894 DOI: 10.1016/j.biopha.2023.115627] [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: 07/25/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Tumors of the gastrointestinal tract impose a substantial healthcare burden due to their prevalence and challenging prognosis. METHODS We conducted a review of peer-reviewed scientific literature using reputable databases (PubMed, Scopus, Web of Science) with a focus on oncolytic virus therapy within the context of gastrointestinal tumors. Our search covered the period up to the study's completion in June 2023. INCLUSION AND EXCLUSION CRITERIA This study includes articles from peer-reviewed scientific journals, written in English, that specifically address oncolytic virus therapy for gastrointestinal tumors, encompassing genetic engineering advances, combined therapeutic strategies, and safety and efficacy concerns. Excluded are articles not meeting these criteria or focusing on non-primary gastrointestinal metastatic tumors. RESULTS Our review revealed the remarkable specificity of oncolytic viruses in targeting tumor cells and their potential to enhance anti-tumor immune responses. However, challenges related to safety and efficacy persist, underscoring the need for ongoing research and improvement. CONCLUSION This study highlights the promising role of oncolytic virus therapy in enhancing gastrointestinal tumor treatments. Continued investigation and innovative combination therapies hold the key to reducing the burden of these tumors on patients and healthcare systems.
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Affiliation(s)
- Yang Li
- General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China; School of Nursing, Jilin University, Changchun, China
| | - Hao-Yu Duan
- General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Kai-di Yang
- School of Nursing, Jilin University, Changchun, China
| | - Jun-Feng Ye
- General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China.
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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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Zhu X, Fan C, Xiong Z, Chen M, Li Z, Tao T, Liu X. Development and application of oncolytic viruses as the nemesis of tumor cells. Front Microbiol 2023; 14:1188526. [PMID: 37440883 PMCID: PMC10335770 DOI: 10.3389/fmicb.2023.1188526] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/18/2023] [Indexed: 07/15/2023] Open
Abstract
Viruses and tumors are two pathologies that negatively impact human health, but what occurs when a virus encounters a tumor? A global consensus among cancer patients suggests that surgical resection, chemotherapy, radiotherapy, and other methods are the primary means to combat cancer. However, with the innovation and development of biomedical technology, tumor biotherapy (immunotherapy, molecular targeted therapy, gene therapy, oncolytic virus therapy, etc.) has emerged as an alternative treatment for malignant tumors. Oncolytic viruses possess numerous anti-tumor properties, such as directly lysing tumor cells, activating anti-tumor immune responses, and improving the tumor microenvironment. Compared to traditional immunotherapy, oncolytic virus therapy offers advantages including high killing efficiency, precise targeting, and minimal side effects. Although oncolytic virus (OV) therapy was introduced as a novel approach to tumor treatment in the 19th century, its efficacy was suboptimal, limiting its widespread application. However, since the U.S. Food and Drug Administration (FDA) approved the first OV therapy drug, T-VEC, in 2015, interest in OV has grown significantly. In recent years, oncolytic virus therapy has shown increasingly promising application prospects and has become a major research focus in the field of cancer treatment. This article reviews the development, classification, and research progress of oncolytic viruses, as well as their mechanisms of action, therapeutic methods, and routes of administration.
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Affiliation(s)
- Xiao Zhu
- Zhejiang Provincial People's Hospital Affiliated to Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
- Department of Biological and Chemical Sciences, New York Institute of Technology—Manhattan Campus, New York, NY, United States
| | - Chenyang Fan
- Department of Clinical Medicine, Medicine and Technology, School of Zunyi Medical University, Zunyi, China
| | - Zhuolong Xiong
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Mingwei Chen
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital(Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Tao Tao
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Xiuqing Liu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
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Yamada T, Tateishi R, Iwai M, Tanaka M, Ijichi H, Sano M, Koike K, Todo T. Overcoming resistance of stroma-rich pancreatic cancer with focal adhesion kinase inhibitor combined with G47Δ and immune checkpoint inhibitors. Mol Ther Oncolytics 2022; 28:31-43. [PMID: 36619294 PMCID: PMC9801088 DOI: 10.1016/j.omto.2022.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease known for its dense tumor stroma. Focal adhesion kinase inhibitor (FAKi), a non-receptor type tyrosine kinase inhibitor, reduces the tumor stroma. G47Δ, a third-generation oncolytic herpes simplex virus type 1, destroys tumor cells selectively and induces antitumor immune responses. This study evaluates the efficacy of FAKi and G47Δ in PDAC models in combination with or without immune checkpoint inhibitors. G47Δ was effective in human PDAC cell lines in vitro and in subcutaneous as well as orthotopic tumor models. Transgenic mouse-derived #146 cells were used to generate subcutaneous PDAC tumors with rich stroma in immunocompetent mice. In this #146 tumor model, the efficacy of FAKi was synergistically augmented when combined with G47Δ, which reflected not only a decreased stromal content but also a significant shifting of the tumor microenvironment toward immune stimulation. In transgenic autochthonous PKF mice, a rare model that develops stroma-rich PDAC with a 100% penetrance and resembles human PDAC in various aspects, the prolongation of survival compared with FAKi alone was achieved only when FAKi was combined with G47Δ and immune checkpoint inhibitors. The FAKi combination therapy may be useful to overcome the treatment resistance of stroma-rich PDAC.
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Affiliation(s)
- Tomoharu Yamada
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Miwako Iwai
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Minoru Tanaka
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Hideaki Ijichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Makoto Sano
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,Corresponding author Tomoki Todo, M.D., Ph.D., Division of Innovative Cancer Therapy, Advanced Clinical Research Center, and Department of Surgical Neuro-Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
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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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13
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Li Z, Feiyue Z, Gaofeng L, Haifeng L. Lung cancer and oncolytic virotherapy--enemy's enemy. Transl Oncol 2022; 27:101563. [PMID: 36244134 PMCID: PMC9561464 DOI: 10.1016/j.tranon.2022.101563] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/27/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022] Open
Abstract
Lung cancer is one of the malignant tumors that seriously threaten human health worldwide, while the covid-19 virus has become people's nightmare after the coronavirus pandemic. There are too many similarities between cancer cells and viruses, one of the most significant is that both of them are our enemies. The strategy to take the advantage of the virus to beat cancer cells is called Oncolytic virotherapy. When immunotherapy represented by immune checkpoint inhibitors has made remarkable breakthroughs in the clinical practice of lung cancer, the induction of antitumor immunity from immune cells gradually becomes a rapidly developing and promising strategy of cancer therapy. Oncolytic virotherapy is based on the same mechanisms that selectively kill tumor cells and induce systemic anti-tumor immunity, but still has a long way to go before it becomes a standard treatment for lung cancer. This article provides a comprehensive review of the latest progress in oncolytic virotherapy for lung cancer, including the specific mechanism of oncolytic virus therapy and the main types of oncolytic viruses, and the combination of oncolytic virotherapy and existing standard treatments. It aims to provide new insights and ideas on oncolytic virotherapy for lung cancer.
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Affiliation(s)
- Zhang Li
- Department of Oncology, Gejiu People's Hospital, The Fifth Affiliated Hospital of Kunming Medical University, China
| | - Zhang Feiyue
- Department of Oncology, Yuxi People's Hospital, The Sixth Affiliated Hospital of Kunming Medical University, China
| | - Li Gaofeng
- Department of Thoracic Surgery, Yunnan Cancer Center, The Third Affiliated Hospital of Kunming Medical University, China
| | - Liang Haifeng
- Department of Oncology, Gejiu People's Hospital, The Fifth Affiliated Hospital of Kunming Medical University, China,Corresponding author.
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14
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Scanlan H, Coffman Z, Bettencourt J, Shipley T, Bramblett DE. Herpes simplex virus 1 as an oncolytic viral therapy for refractory cancers. Front Oncol 2022; 12:940019. [PMID: 35965554 PMCID: PMC9364694 DOI: 10.3389/fonc.2022.940019] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022] Open
Abstract
The need for efficacious and non-toxic cancer therapies is paramount. Oncolytic viruses (OVs) are showing great promise and are introducing new possibilities in cancer treatment with their ability to selectively infect tumor cells and trigger antitumor immune responses. Herpes Simplex Virus 1 (HSV-1) is a commonly selected OV candidate due to its large genome, relative safety profile, and ability to infect a variety of cell types. Talimogene laherparevec (T-VEC) is an HSV-1-derived OV variant and the first and only OV therapy currently approved for clinical use by the United States Food and Drug Administration (FDA). This review provides a concise description of HSV-1 as an OV candidate and the genomic organization of T-VEC. Furthermore, this review focuses on the advantages and limitations in the use of T-VEC compared to other HSV-1 OV variants currently in clinical trials. In addition, approaches for future directions of HSV-1 OVs as cancer therapy is discussed.
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Affiliation(s)
- Hayle Scanlan
- Rowan School of Medicine, RowanSOM-Jefferson Health-Virtua Our Lady of Lourdes Hospital, Stratford, NJ, United States
| | - Zachary Coffman
- Monroe Clinic Rural Family Medicine Program, The University of Illinois College of Medicine Rockford, Monroe, WI, United States
| | - Jeffrey Bettencourt
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
| | - Timothy Shipley
- Department of Biomedical Sciences, A.T. Still University School of Osteopathic Medicine in Arizona, Mesa, AZ, United States
| | - Debra E. Bramblett
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
- *Correspondence: Debra E. Bramblett,
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15
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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: 15] [Impact Index Per Article: 5.0] [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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16
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Luo W, Wang Y, Zhang T. Win or loss? Combination therapy does improve the oncolytic virus therapy to pancreatic cancer. Cancer Cell Int 2022; 22:160. [PMID: 35443724 PMCID: PMC9022249 DOI: 10.1186/s12935-022-02583-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 04/11/2022] [Indexed: 11/10/2022] Open
Abstract
Pancreatic cancer (PC) is a growing global burden, remaining one of the most lethal cancers of the gastrointestinal tract. Moreover, PC is resistant to various treatments such as chemotherapy, radiotherapy, and immunotherapy. New therapies are urgently needed to improve the prognosis of PC. Oncolytic virus (OV) therapy is a promising new treatment option. OV is a genetically modified virus that selectively replicates in tumor cells. It can kill tumor cells without harming normal cells. The activation of tumor-specific T-cells is a unique feature of OV-mediated therapy. However, OV-mediated mono-therapeutic efficacy remains controversial, especially for metastatic or advanced patients who require systemically deliverable therapies. Hence, combination therapies will be critical to improve the therapeutic efficacy of OV-mediated therapy and prevent tumor recurrence. This review aims to investigate novel combinatorial treatments with OV therapy and explore the inner mechanism of those combined therapies, hopefully providing a new direction for a better prognosis of PC.
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Affiliation(s)
- Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Yawen Wang
- Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Key Laboratory of Endocrinology of National Health Commission of the People's Republic of China, The Translational Medicine Center of Peking Union Medical College Hospital (PUMCH), PUMCH, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. .,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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17
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Hamidi-Sofiani V, Rakhshi R, Moradi N, Zeynali P, Nakhaie M, Behboudi E. Oncolytic viruses and pancreatic cancer. Cancer Treat Res Commun 2022; 31:100563. [PMID: 35460973 DOI: 10.1016/j.ctarc.2022.100563] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Today, the pancreatic cancer prognosis is poor and genetic technology is developing to treat various types of cancers. Scientists are actively looking for a new technique to design a therapeutic strategy to treat pancreatic cancer. Several oncolytic viruses are known to be valuable tools for pancreatic cancer treatment. Recent Studies demonstrate their effectiveness and safety in various administration routes such as direct intratumoral, intracutaneous, intravascular, and other routes. METHOD In this study, all studies conducted in the past 20 years have been reviewed. Reputable scientific databases including Irandoc, Scopus, Google Scholar and PubMed, are searched for the keywords of Pancreatic cancer, oncolytic, viruses and treatment and the latest information about them is obtained. RESULTS Engineering the oncolytic viruses' genome and insertion of intended transgenes including cytokines or shRNAs, has caused promising promotions in pancreatic cancer treatment. Some oncolytic viruses inhibit tumors directly and some through activation of immune responses. CONCLUSION This approach showed some signs of success in efficiency like immune system activation in the tumor environment, effective virus targeting in the tumor cells by systemic administration, and enhanced patient survival in comparison with the control group. But of course, until now, using these oncolytic viruses alone has not been effective in elimination of tumors.
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Affiliation(s)
| | - Reza Rakhshi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Niloufar Moradi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Parisa Zeynali
- Department of Biochemistry and Biophysics, Metabolic Disorders Research Center, School of Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Mohsen Nakhaie
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
| | - Emad Behboudi
- Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran.
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18
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Gao P, Ding G, Wang L. The efficacy and safety of oncolytic viruses in the treatment of intermediate to advanced solid tumors: a systematic review and meta-analysis. Transl Cancer Res 2022; 10:4290-4302. [PMID: 35116288 PMCID: PMC8799180 DOI: 10.21037/tcr-21-905] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022]
Abstract
Background Cancer treatment remains one of the most formidable challenges worldwide. Some novel treatment strategies, including molecularly targeted therapy, gene therapy, and cellular immunotherapy, have also been investigated to improve therapeutic effects for cancer patients and have demonstrated unexpected positive effects. This systematic review and meta-analysis evaluated the efficacy and safety of oncolytic virus (OV) monotherapy or combination therapy for intermediate to advanced solid tumors. Methods We retrieved articles from PubMed, Embase, Web of Science, CNKI, Wanfang and VIP. The quality of the included studies was assessed by Review Manager Software version 5.3. STATA software was used to perform meta-analyses of efficacy, overall survival (OS) and adverse reactions. Results A total of 22 studies involving 3,996 patients were included in this analysis, including 13 H101 studies, 5 T-VEC studies, 2 Pexa-Vec studies, 1 HF10 study and 1 Reolysin study. Regarding oncolytic adenovirus H101, meta-analysis showed that patients treated with H101 monotherapy or H101 combined with chemotherapy had a significantly higher objective response rate (ORR) than those treated with chemotherapy. Patients in the H101 and T-VEC groups had significantly longer effect size (ES) than the control group patients. The odds ratio (OR) and ES of patients with hepatocellular carcinoma, lung cancer and melanoma treated with OV were analyzed. For the safety profile, the total incidence of adverse reactions was similar in both groups. In terms of the other OVs, according to a systematic review, we found that after Reolysin treatment, the ORR was 26.9% in patients with head and neck cancer. The phase I study of HF10 exhibited some therapeutic potential. The adverse events (AEs) associated with the other OVs mainly included fever, nausea and vomiting, leukopenia, and hypotension. Discussion OVs are effective and well tolerated for the treatment of intermediate to advanced solid cancer and represent a promising therapeutic approach for solid cancers.
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Affiliation(s)
- Peng Gao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Guanxiong Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Lujia Wang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
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19
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Mozaffari Nejad AS, Fotouhi F, Mehrbod P, Alikhani MY. Antitumor immunity enhancement through Newcastle viral oncolysate in mice model: A promising method to treat tumors. Saudi J Biol Sci 2021; 28:5833-5840. [PMID: 34588898 PMCID: PMC8459063 DOI: 10.1016/j.sjbs.2021.06.043] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 06/09/2021] [Accepted: 06/13/2021] [Indexed: 12/30/2022] Open
Abstract
A Newcastle disease virus (NDV) oncolysate has been established as a unique and effective immune-stimulatory root for tumor treatment. Thus, the aim of the current study was to investigate the effects of intratumoral administration of NDV oncolysate on immune response and tumor regression of C57BL/6 mouse model of human papillomavirus (HPV) related transplanted with TC-1 syngeneic cancer cells. To further investigate the mechanism underlying the antitumor response, cytolytic and lymphocyte proliferation responses in splenocytes were measured using lactate dehydrogenase (LDH) release and MTT assays, respectively. In this regard, levels of IL-10, IFN-γ, and IL-4 were measured using ELISA after re-stimulation. The immune responses efficacy was evaluated by in vivo tumor regression assay. The results showed that immunization with the different titers of NDV lysate significantly reduced tumor volume in comparison with a combination of virus lysate and tumor cell lysate. Also, virus lysate could significantly enhance cytotoxic T lymphocyte production and lymphocyte proliferation rates versus tumor cell lysate. Also, our major findings are that the peritumorally injection of NDV oncolysate effectively induces antitumor immune responses through increased levels of IL-4, IFN-γ, and reduction of IL-10. These results indicate that this treatment is a specific, active immune mechanism stimulator, and may prove to be a useful therapeutic for a treatment against cervical cancers and merits further investigation.
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Key Words
- DAMP, Danger-associated molecular pattern
- ELISA, Enzyme-Linked Immunosorbent Assay
- FBS, Fetal bovine serum
- FDA, Food and drug administration
- HB1, Hitchner B1
- HPV, Human papillomavirus
- Human papillomavirus
- LDH, Lactate dehydrogenase
- MOI, Multiplicity of infection
- NDV, Newcastle disease virus
- Newcastle disease virus
- OVs, Oncolytic viruses
- Oncolysate
- Oncolytic
- PBS, Phosphate-buffered saline
- RPMI, Roswell park memorial institute
- T-Vec, Talimogene laherparepvec
- Tumor microenvironment
- UVB, Ultraviolet B
- VO, Viral oncolysate
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Affiliation(s)
| | - Fatemeh Fotouhi
- Influenza and Respiratory Viruses Department, Pasteur Institute of Iran, Tehran, Iran
| | - Parvaneh Mehrbod
- Influenza and Respiratory Viruses Department, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammad Yousef Alikhani
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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20
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Santos Apolonio J, Lima de Souza Gonçalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, de Souza WR, Sande Loureiro M, de Melo FF. Oncolytic virus therapy in cancer: A current review. World J Virol 2021; 10:229-255. [PMID: 34631474 PMCID: PMC8474975 DOI: 10.5501/wjv.v10.i5.229] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.
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Affiliation(s)
- Jonathan Santos Apolonio
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - João Victor Silva Souza
- Universidade Estadual do Sudoeste da Bahia, Campus Vitória da Conquista, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Wedja Rafaela de Souza
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45029-094, Bahia, Brazil
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21
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Jahan N, Ghouse SM, Martuza RL, Rabkin SD. In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV. Viruses 2021; 13:v13091740. [PMID: 34578321 PMCID: PMC8473045 DOI: 10.3390/v13091740] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
Herpes simplex virus (HSV) can be genetically altered to acquire oncolytic properties so that oncolytic HSV (oHSV) preferentially replicates in and kills cancer cells, while sparing normal cells, and inducing anti-tumor immune responses. Over the last three decades, a better understanding of HSV genes and functions, and improved genetic-engineering techniques led to the development of oHSV as a novel immunovirotherapy. The concept of in situ cancer vaccination (ISCV) was first introduced when oHSV was found to induce a specific systemic anti-tumor immune response with an abscopal effect on non-injected tumors, in the process of directly killing tumor cells. Thus, the use of oHSV for tumor vaccination in situ is antigen-agnostic. The research and development of oHSVs have moved rapidly, with the field of oncolytic viruses invigorated by the FDA/EMA approval of oHSV talimogene laherparepvec in 2015 for the treatment of advanced melanoma. Immunovirotherapy can be enhanced by arming oHSV with immunomodulatory transgenes and/or using them in combination with other chemotherapeutic and immunotherapeutic agents. This review offers an overview of the development of oHSV as an agent for ISCV against solid tumors, describing the multitude of different oHSVs and their efficacy in immunocompetent mouse models and in clinical trials.
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Affiliation(s)
- Nusrat Jahan
- Molecular Neurosurgery Laboratory and Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (N.J.); (S.M.G.); (R.L.M.)
| | - Shanawaz M. Ghouse
- Molecular Neurosurgery Laboratory and Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (N.J.); (S.M.G.); (R.L.M.)
| | - Robert L. Martuza
- Molecular Neurosurgery Laboratory and Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (N.J.); (S.M.G.); (R.L.M.)
| | - Samuel D. Rabkin
- Department of Neurosurgery, Massachusetts General Hospital, 185 Cambridge St., CPZN-3800, Boston, MA 02114, USA
- Correspondence:
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22
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Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers (Basel) 2021; 13:cancers13164138. [PMID: 34439292 PMCID: PMC8393975 DOI: 10.3390/cancers13164138] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.
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23
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The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment. Viruses 2021; 13:v13071200. [PMID: 34206677 PMCID: PMC8310320 DOI: 10.3390/v13071200] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.
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24
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Morimoto D, Matsumura S, Bustos-Villalobos I, Sibal PA, Ichinose T, Naoe Y, Eissa IR, Abdelmoneim M, Mukoyama N, Miyajima N, Tanaka M, Kodera Y, Kasuya H. C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells. Cells 2021; 10:cells10061502. [PMID: 34203706 PMCID: PMC8232185 DOI: 10.3390/cells10061502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 11/16/2022] Open
Abstract
Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)-TBK1-IRF3-IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS-STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.
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Affiliation(s)
- Daishi Morimoto
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (D.M.); (I.R.E.); (M.A.); (Y.K.)
| | - Shigeru Matsumura
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
| | - Itzel Bustos-Villalobos
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
| | - Patricia Angela Sibal
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
- Department of Biological Science, School of Science, Nagoya University, Nagoya 466-8550, Japan
| | - Toru Ichinose
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
| | - Yoshinori Naoe
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
| | - Ibrahim Ragab Eissa
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (D.M.); (I.R.E.); (M.A.); (Y.K.)
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
- Faculty of Science, Tanta University, Tanta 31111, Egypt
| | - Mohamed Abdelmoneim
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (D.M.); (I.R.E.); (M.A.); (Y.K.)
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
- Department of Microbiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Nobuaki Mukoyama
- Department of Otolaryngology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan;
| | - Noriyuki Miyajima
- Department of Transplantation and Endocrine Surgery, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan;
| | - Maki Tanaka
- Takara Bio Inc., Kusatsu, Shiga 525-0058, Japan;
| | - Yasuhiro Kodera
- Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (D.M.); (I.R.E.); (M.A.); (Y.K.)
| | - Hideki Kasuya
- Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (S.M.); (I.B.-V.); (P.A.S.); (T.I.); (Y.N.)
- Correspondence:
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Lin W, Zhao Y, Zhong L. Current strategies of virotherapy in clinical trials for cancer treatment. J Med Virol 2021; 93:4668-4692. [PMID: 33738818 DOI: 10.1002/jmv.26947] [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: 11/28/2020] [Revised: 02/12/2021] [Accepted: 03/15/2021] [Indexed: 12/19/2022]
Abstract
As a novel immune-active agent for cancer treatment, viruses have the ability of infecting and replicating in tumor cells. The safety and efficacy of viruses has been tested and confirmed in preclinical and clinical trials. In the last decade, virotherapy has been adopted as a monotherapy or combined therapy with immunotherapy, chemotherapy, or radiotherapy, showing promising outcomes against cancer. In this review, the current strategies of viruses used in clinical trials are classified and described. Besides this, the challenge and future prospects of virotherapy in the management for cancer patients are discussed in this review.
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Affiliation(s)
- Weijian Lin
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Yongxiang Zhao
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Liping Zhong
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China
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Zhang B, Huang J, Tang J, Hu S, Luo S, Luo Z, Zhou F, Tan S, Ying J, Chang Q, Zhang R, Geng C, Wu D, Gu X, Liu B. Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial. J Immunother Cancer 2021; 9:jitc-2020-002224. [PMID: 33837053 PMCID: PMC8043042 DOI: 10.1136/jitc-2020-002224] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors. METHODS In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II. RESULTS Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline. CONCLUSIONS Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.
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Affiliation(s)
- Bo Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Huang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China .,Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jialin Tang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Sheng Hu
- Department of Thoracic Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suxia Luo
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Zhiguo Luo
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Fuxiang Zhou
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shiyun Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jieer Ying
- Department of Abdominal Oncology, Institute of Cancer Research & Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Qing Chang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Zhang
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengyun Geng
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dawei Wu
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | - Binlei Liu
- Binhui Biopharmaceutical Co., Ltd, Wuhan, China.,National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China
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Miyazawa M, Katsuda M, Kawai M, Hirono S, Okada KI, Kitahata Y, Yamaue H. Advances in immunotherapy for pancreatic ductal adenocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:419-430. [PMID: 33742512 DOI: 10.1002/jhbp.944] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Advances in immunotherapy against advanced cancers can be considered stunning and epoch-making. Meanwhile, efficacy of immune-based therapies, especially immune checkpoint inhibitors, remains insufficient in pancreatic ductal adenocarcinoma, differing from other immunogenic cancers. To date, neither immunotherapies targeting immune system acceleration nor release of immunologic brakes have been able to overcome the robust immune barrier in the pancreatic tumor microenvironment, which is characterized by rich fibrotic stroma and accumulation of immunosuppressive myeloid cells. However, by receiving an immune checkpoint blockade, patients with abundant tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma clearly have better prognosis, and patients with mismatch repair deficiency have achieved better outcomes, albeit in a small population of pancreatic ductal adenocarcinoma. We overview recent preclinical and clinical studies that have been concerned with immune-based therapies including cancer vaccine and immune checkpoint inhibitors. By providing a deep insight into the immunosuppressive tumor microenvironment, we suggest the possibility of comprehensive immune intensification that could reverse the tumor microenvironment, making it conducive to cytotoxic T lymphocyte activity for overcoming pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Motoki Miyazawa
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Masahiro Katsuda
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Manabu Kawai
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Seiko Hirono
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Ken-Ichi Okada
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yuji Kitahata
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
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Brouwer TP, Vahrmeijer AL, de Miranda NFCC. Immunotherapy for pancreatic cancer: chasing the light at the end of the tunnel. Cell Oncol (Dordr) 2021; 44:261-278. [PMID: 33710604 PMCID: PMC7985121 DOI: 10.1007/s13402-021-00587-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Checkpoint blockade immunotherapy has had a significant impact on the survival of a subset of patients with advanced cancers. It has been particularly effective in immunogenic cancer types that present large numbers of somatic mutations in their genomes. To date, all conventional immunotherapies have failed to produce significant clinical benefits for patients diagnosed with pancreatic cancer, probably due to its poor immunogenic properties, including low numbers of neoantigens and highly immune-suppressive microenvironments. CONCLUSIONS Herein, we discuss advances that have recently been made in cancer immunotherapy and the potential of this field to deliver effective treatment options for pancreatic cancer patients. Preclinical investigations, combining different types of therapies, highlight possibilities to enhance anti-tumor immunity and to generate meaningful clinical responses in pancreatic cancer patients. Results from completed and ongoing (pre)clinical trials are discussed.
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Affiliation(s)
- Thomas P Brouwer
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands, PO Box 9600, 2300 RC
| | | | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands, PO Box 9600, 2300 RC.
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Koch MS, Lawler SE, Chiocca EA. HSV-1 Oncolytic Viruses from Bench to Bedside: An Overview of Current Clinical Trials. Cancers (Basel) 2020; 12:E3514. [PMID: 33255871 PMCID: PMC7760226 DOI: 10.3390/cancers12123514] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/18/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022] Open
Abstract
Herpes simplex virus 1 (HSV-1) provides a genetic chassis for several oncolytic viruses (OVs) currently in clinical trials. Oncolytic HSV1 (oHSV) have been engineered to reduce neurovirulence and enhance anti-tumor lytic activity and immunogenicity to make them attractive candidates in a range of oncology indications. Successful clinical data resulted in the FDA-approval of the oHSV talimogene laherparepvec (T-Vec) in 2015, and several other variants are currently undergoing clinical assessment and may expand the landscape of future oncologic therapy options. This review offers a detailed overview of the latest results from clinical trials as well as an outlook on newly developed HSV-1 oncolytic variants with improved tumor selectivity, replication, and immunostimulatory capacity and related clinical studies.
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Affiliation(s)
| | - Sean E. Lawler
- Harvey Cushing Neurooncology Research Laboratories, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.S.K.); (E.A.C.)
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Cook M, Chauhan A. Clinical Application of Oncolytic Viruses: A Systematic Review. Int J Mol Sci 2020; 21:ijms21207505. [PMID: 33053757 PMCID: PMC7589713 DOI: 10.3390/ijms21207505] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023] Open
Abstract
Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development.
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Affiliation(s)
- Mary Cook
- Department of Internal Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, 22 S. Greene Street, Baltimore, MD 21201, USA;
| | - Aman Chauhan
- Department of Internal Medicine-Medical Oncology, University of Kentucky, Lexington, KY 40536, USA
- Markey Cancer Center, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA
- Correspondence: ; Tel.: +504-278-0134
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31
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Radosa JC, Stotz L, Müller C, Kaya AC, Solomayer EF, Radosa MP. Clinical Data on Immunotherapy in Breast Cancer. Breast Care (Basel) 2020; 15:450-469. [PMID: 33223989 PMCID: PMC7650095 DOI: 10.1159/000511788] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Breast cancer has traditionally been considered to have a low immunogenic potential compared to other tumor entities. SUMMARY The most extensively studied immunotherapeutic agents for breast cancer to date are immune checkpoint inhibitors, with the results of the IMpassion130 trial leading to the approval of atezolizumab plus nab-paclitaxel for first-line treatment of programmed cell death ligand 1-positive, metastatic, triple-negative breast cancer, and studies in earlier stages have yielded promising results. Other immunotherapeutic options being assessed in phases 2 and 3 trials include vaccine-based therapies and treatment with anti-human epidermal growth factor receptor 2 (H-directed immune-linked antibodies) and substances evaluated in early clinical trials as cellular therapies (adoptive cell therapy and chimeric antigen receptor T cells). KEY MESSAGES Immunotherapy is an emerging modality for the treatment of breast cancer, as evidenced by the plethora of preclinical and clinical concepts and ongoing trials. Early studies established the role of immunotherapeutic agents in the metastatic setting. Ongoing studies will expand our knowledge about the timing of administration, best partners for combination therapy, and predictive biomarkers to guide immunotherapy for breast cancer.
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Affiliation(s)
- Julia Caroline Radosa
- Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg, Germany
| | - Lisa Stotz
- Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg, Germany
| | - Carolin Müller
- Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg, Germany
| | - Askin Canguel Kaya
- Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg, Germany
| | - Erich-Franz Solomayer
- Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg, Germany
| | - Marc Philipp Radosa
- Department of Gynecology and Obstetrics, Klinikum Bremen-Nord, Bremen, Germany
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de Graaf JF, Huberts M, Fouchier RAM, van den Hoogen BG. Determinants of the efficacy of viro-immunotherapy: A review. Cytokine Growth Factor Rev 2020; 56:124-132. [PMID: 32919831 DOI: 10.1016/j.cytogfr.2020.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 07/02/2020] [Indexed: 10/23/2022]
Abstract
Oncolytic virus immunotherapy is rapidly gaining interest in the field of immunotherapy against cancer. The minimal toxicity upon treatment and the dual activity of direct oncolysis and immune activation make therapy with oncolytic viruses (OVs) an interesting treatment modality. The safety and efficacy of several OVs have been assessed in clinical trials and, so far, the Food and Drug Administration (FDA) has approved one OV. Unfortunately, most treatments with OVs have shown suboptimal responses in clinical trials, while they appeared more promising in preclinical studies, with tumours reducing after immune cell influx. In several clinical trials with OVs, parameters such as virus replication, virus-specific antibodies, systemic immune responses, immune cell influx into tumours and tumour-specific antibodies have been studied as predictors or correlates of therapy efficacy. In this review, these studies are summarized to improve our understanding of the determinants of the efficacy of OV therapies in humans and to provide insights for future developments in the viro-immunotherapy treatment field.
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Affiliation(s)
- J F de Graaf
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, The Netherlands
| | - M Huberts
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, The Netherlands
| | - R A M Fouchier
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, The Netherlands
| | - B G van den Hoogen
- Viroscience Department, Erasmus Medical Centrum, Rotterdam, The Netherlands.
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Hwang JS, Joo HD, Song TJ. Endoscopic Ultrasound-Guided Local Therapy for Pancreatic Neoplasms. Clin Endosc 2020; 53:535-540. [PMID: 33027583 PMCID: PMC7548142 DOI: 10.5946/ce.2020.181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/07/2020] [Accepted: 09/17/2020] [Indexed: 12/18/2022] Open
Abstract
Surgical resection is considered the only treatment option for pancreatic cancer and other pancreatic neoplasms with malignant potential, such as neuroendocrine tumors, mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms. However, only 10%-20% of all patients with pancreatic cancer present with resectable forms of the disease as the symptoms are rarely manifested during the early stages, and the disease tends to progress rapidly. Furthermore, pancreatic surgery is associated with high rates of morbidity and mortality. The development of linear-array endoscopic ultrasound (EUS) techniques has increased the indications of EUS-guided local therapy for pancreatic neoplasms. We assessed the studies that investigated various treatment modalities, such as fine-needle injection, radiofrequency ablation, irreversible electroporation, and radiotherapy, under EUS guidance to better understand the usefulness of these techniques with respect to the efficacy and associated complications.
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Affiliation(s)
- Jun Seong Hwang
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Hyun Don Joo
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae Jun Song
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Huang A, Pressnall MM, Lu R, Huayamares SG, Griffin JD, Groer C, DeKosky BJ, Forrest ML, Berkland CJ. Human intratumoral therapy: Linking drug properties and tumor transport of drugs in clinical trials. J Control Release 2020; 326:203-221. [PMID: 32673633 DOI: 10.1016/j.jconrel.2020.06.029] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 01/08/2023]
Abstract
Cancer therapies aim to kill tumor cells directly or engage the immune system to fight malignancy. Checkpoint inhibitors, oncolytic viruses, cell-based immunotherapies, cytokines, and adjuvants have been applied to prompt the immune system to recognize and attack cancer cells. However, systemic exposure of cancer therapies can induce unwanted adverse events. Intratumoral administration of potent therapies utilizes small amounts of drugs, in an effort to minimize systemic exposure and off-target toxicities. Here, we discuss the properties of the tumor microenvironment and transport considerations for intratumoral drug delivery. Specifically, we consider various tumor tissue factors and physicochemical factors that can affect tumor retention after intratumoral injection. We also review approved and clinical-stage intratumoral therapies and consider how the molecular and biophysical properties (e.g. size and charge) of these therapies influences intratumoral transport (e.g. tumor retention and cellular uptake). Finally, we offer a critical review and highlight several emerging approaches to promote tumor retention and limit systemic exposure of potent intratumoral therapies.
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Affiliation(s)
- Aric Huang
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Melissa M Pressnall
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Ruolin Lu
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | | | - J Daniel Griffin
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA; Bioengineering Graduate Program, University of Kansas, Lawrence, KS, USA
| | | | - Brandon J DeKosky
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA; Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS, USA
| | - M Laird Forrest
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA
| | - Cory J Berkland
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA; Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS, USA; Bioengineering Graduate Program, University of Kansas, Lawrence, KS, USA.
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35
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Scherwitzl I, Opp S, Hurtado AM, Pampeno C, Loomis C, Kannan K, Yu M, Meruelo D. Sindbis Virus with Anti-OX40 Overcomes the Immunosuppressive Tumor Microenvironment of Low-Immunogenic Tumors. Mol Ther Oncolytics 2020; 17:431-447. [PMID: 32478167 PMCID: PMC7251545 DOI: 10.1016/j.omto.2020.04.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 04/29/2020] [Indexed: 01/03/2023] Open
Abstract
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to therapies. It is now clear that elevated levels of tumor-infiltrating T cells as well as a systemic anti-tumor immune response are requirements for successful immunotherapies. However, the tumor microenvironment imposes an additional resistance mechanism to immunotherapy. We have developed a practical and improved strategy for cancer immunotherapy using an oncolytic virus and anti-OX40. This strategy takes advantage of a preexisting T cell immune repertoire in vivo, removing the need to know about present tumor antigens. We have shown in this study that the replication-deficient oncolytic Sindbis virus vector expressing interleukin-12 (IL-12) (SV.IL12) activates immune-mediated tumor killing by inducing OX40 expression on CD4 T cells, allowing the full potential of the agonistic anti-OX40 antibody. The combination of SV.IL12 with anti-OX40 markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated terminally differentiated effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity capable of overcoming the repressive tumor microenvironment. Our findings identify SV.IL12 in combination with anti-OX40 to be a novel and potent therapeutic strategy that can cure multiple types of low-immunogenic solid tumors.
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Affiliation(s)
- Iris Scherwitzl
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Silvana Opp
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | | | | | - Cynthia Loomis
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Kasthuri Kannan
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Minjun Yu
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Daniel Meruelo
- Department of Pathology, NYU School of Medicine, New York, NY, USA
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Terrível M, Gromicho C, Matos AM. Oncolytic viruses: what to expect from their use in cancer treatment. Microbiol Immunol 2020; 64:477-492. [PMID: 31663631 DOI: 10.1111/1348-0421.12753] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/18/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023]
Abstract
Oncolytic viruses are biologic agents able to selectively infect and destroy cancer cells while sparing the normal ones. Furthermore, they also stimulate the host immune system to combat the tumor growth and to promote tumor removal. This review thoroughly describes different types of viruses developed for targeting specific cancers, as well as the strategies to improve the efficacy and safety of oncolytic virotherapy. It also explores how their potential as anticancer agents may be enhanced through combination with other traditional therapies, such as chemotherapy or more recent approaches, such as checkpoint inhibitors. There are many oncolytic viruses currently being tested in clinical trials for the treatment of various types of cancer, suggesting that this approach could become the near future of the oncology field.
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Affiliation(s)
| | | | - Ana Miguel Matos
- Laboratory of Microbiology, Faculty of Pharmacy, Centre on Chemical Processes Engineering and Forest Products (CIEPQF), University of Coimbra, Portugal
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Li L, Liu S, Han D, Tang B, Ma J. Delivery and Biosafety of Oncolytic Virotherapy. Front Oncol 2020; 10:475. [PMID: 32373515 PMCID: PMC7176816 DOI: 10.3389/fonc.2020.00475] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/16/2020] [Indexed: 12/19/2022] Open
Abstract
In recent years, oncolytic virotherapy has emerged as a promising anticancer therapy. Oncolytic viruses destroy cancer cells, without damaging normal tissues, through virus self-replication and antitumor immunity responses, showing great potential for cancer treatment. However, the clinical guidelines for administering oncolytic virotherapy remain unclear. Delivery routes for oncolytic virotherapy to patients vary in existing studies, depending on the tumor sites and the objective of studies. Moreover, the biosafety of oncolytic virotherapy, including mainly uncontrolled adverse events and long-term complications, remains a serious concern that needs to be accurately measured. This review provides a comprehensive and detailed overview of the delivery and biosafety of oncolytic virotherapy.
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Affiliation(s)
- Lizhi Li
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Shixin Liu
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Duoduo Han
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Bin Tang
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China
| | - Jian Ma
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, National Health Commission Key Laboratory of Carcinogenesis, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, China
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Alayo QA, Ito H, Passaro C, Zdioruk M, Mahmoud AB, Grauwet K, Zhang X, Lawler SE, Reardon DA, Goins WF, Fernandez S, Chiocca EA, Nakashima H. Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses. Sci Rep 2020; 10:5095. [PMID: 32198420 PMCID: PMC7083912 DOI: 10.1038/s41598-020-61736-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 02/20/2020] [Indexed: 02/05/2023] Open
Abstract
The mode of action for oncolytic viruses (OVs) in cancer treatment is thought to depend on a direct initial cytotoxic effect against infected tumor cells and subsequent activation of immune cell responses directed against the neoplasm. To study both of these effects in a mouse model of glioblastoma (GBM), we employed murine GBM cells engineered to constitutively express the type I Herpes Simplex Virus (HSV1) HSV-1 receptor, nectin-1, to allow for more efficient infection and replication by oncolytic HSV (oHSV). These cells were further engineered with a surrogate tumor antigen to facilitate assays of T cell activity. We utilized MRI-based volumetrics to measure GBM responses after injection with the oHSV and bioluminescent imaging (BLI) to determine oHSV replicative kinetics in the injected tumor mass. We found increased infiltration of both surrogate tumor antigen- and oHSV antigen-specific CD8+ T cells within 7 days after oHSV injection. There was no increase in tumor infiltrating CD8+ T cells expressing “exhaustion” markers, yet oHSV infection led to a reduction in PD-1+ CD8+ T cells in injected GBMs and an increase in IFNγ+ CD8+ T cells. There was a significant direct correlation between oHSV-mediated reduction in GBM volume and increased infiltration of both viral and tumor antigen-specific CD8+ T cells, as well as oHSV intratumoral gene activity. These findings imply that CD8+ T cell cytotoxicity against both tumor and viral antigens as well as intratumoral oHSV gene expression are important in oHSV-mediated GBM therapy.
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Affiliation(s)
- Quazim A Alayo
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA
| | - Hirotaka Ito
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA
| | - Carmela Passaro
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA
| | - Mykola Zdioruk
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA
| | - Ahmad Bakur Mahmoud
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA.,College of Applied Medical Sciences, Taibah University, 42353, Madinah, Saudi Arabia
| | - Korneel Grauwet
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA.,Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, 02114, MA, USA
| | - Xiaoli Zhang
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, 43210, Columbus, OH, USA
| | - Sean E Lawler
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA
| | - David A Reardon
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA
| | - William F Goins
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 15219, Pittsburgh, PA, USA
| | - Soledad Fernandez
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, 43210, Columbus, OH, USA
| | - E Antonio Chiocca
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA.
| | - Hiroshi Nakashima
- Harvey W. Cushing Neuro-oncology Laboratories (HCNL), Department of Neurosurgery, Harvard Medical School and Brigham and Women's Hospital, 02115, Boston, MA, USA.
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Li Y, Shen Y, Zhao R, Samudio I, Jia W, Bai X, Liang T. Oncolytic virotherapy in hepato-bilio-pancreatic cancer: The key to breaking the log jam? Cancer Med 2020; 9:2943-2959. [PMID: 32130786 PMCID: PMC7196045 DOI: 10.1002/cam4.2949] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Traditional therapies have limited efficacy in hepatocellular carcinoma, pancreatic cancer, and biliary tract cancer, especially for advanced and refractory cancers. Through a deeper understanding of antitumor immunity and the tumor microenvironment, novel immunotherapies are becoming available for cancer treatment. Oncolytic virus (OV) therapy is an emerging type of immunotherapy that has demonstrated effective antitumor efficacy in many preclinical studies and clinical studies. Thus, it may represent a potential feasible treatment for hard to treat gastrointestinal (GI) tumors. Here, we summarize the research progress of OV therapy for the treatment of hepato-bilio-pancreatic cancers. In general, most OV therapies exhibits potent, specific oncolysis both in cell lines in vitro and the animal models in vivo. Currently, several clinical trials have suggested that OV therapy may also be effective in patients with refractory hepato-bilio-pancreatic cancer. Multiple strategies such as introducing immunostimulatory genes, modifying virus capsid and combining various other therapeutic modalities have been shown enhanced specific oncolysis and synergistic anti-cancer immune stimulation. Combining OV with other antitumor therapies may become a more effective strategy than using virus alone. Nevertheless, more studies are needed to better understand the mechanisms underlying the therapeutic effects of OV, and to design appropriate dosing and combination strategies.
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Affiliation(s)
- Yuwei Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | | | | | - William Jia
- Virogin Biotech Canada Ltd, Vancouver, Canada
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.,Innovation Center for the study of Pancreatic Diseases, Hangzhou, China
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40
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Mondal M, Guo J, He P, Zhou D. Recent advances of oncolytic virus in cancer therapy. Hum Vaccin Immunother 2020; 16:2389-2402. [PMID: 32078405 DOI: 10.1080/21645515.2020.1723363] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Oncolytic viruses have been taking the front stage in biological therapy for cancer recently. The first and most potent virus to be used in oncolytic virotherapy is human adenovirus. Recently, ongoing extensive research has suggested that other viruses like herpes simplex virus (HSV) and measles virus can also be considered as potential candidates in cancer therapy. An HSV-based oncolytic virus, T-VEC, has completed phase Ш clinical trial and has been approved by the U.S. Food and Drug Administration (FDA) for use in biological cancer therapy. Moreover, the vaccine strain of the measles virus has shown impressive results in pre-clinical and clinical trials. Considering their therapeutic efficacy, safety, and reduced side effects, the use of such engineered viruses in biological cancer therapy has the potential to establish a milestone in cancer research. In this review, we summarize the recent clinical advances in the use of oncolytic viruses in biological therapy for cancer. Additionally, this review evaluates the potential viral candidates for their benefits and shortcomings and sheds light on the future prospects.
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Affiliation(s)
- Moumita Mondal
- Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University , Guangzhou, China.,Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai, China
| | - Jingao Guo
- Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai, China
| | - Ping He
- Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University , Guangzhou, China
| | - Dongming Zhou
- Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences , Shanghai, China
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41
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Taguchi S, Fukuhara H, Todo T. Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives. Jpn J Clin Oncol 2019; 49:201-209. [PMID: 30462296 DOI: 10.1093/jjco/hyy170] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/21/2018] [Indexed: 01/28/2023] Open
Abstract
Oncolytic virus therapy is a promising new option for cancer. It utilizes genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming normal cells. T-VEC (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in 2015 and subsequently approved in Europe in 2016. Other oncolytic viruses using different parental viruses have also been tested in Phase III clinical trials and are ready for drug approval: Pexa-Vec (pexastimogene devacirepvec), an oncolytic vaccinia virus, CG0070, an oncolytic adenovirus, and REOLYSIN (pelareorep), an oncolytic reovirus. In Japan, as of May 2018, several oncolytic viruses have been developed, and some have already proceeded to clinical trials. In this review, we summarize clinical trials assessing oncolytic virus therapy that were conducted or are currently ongoing in Japan, specifically, T-VEC, the abovementioned oncolytic herpes simplex virus type 1, G47Δ, a third-generation oncolytic herpes simplex virus type 1, HF10, a naturally attenuated oncolytic herpes simplex virus type 1, Telomelysin, an oncolytic adenovirus, Surv.m-CRA, another oncolytic adenovirus, and Sendai virus particle. In the near future, oncolytic virus therapy may become an important and major treatment option for cancer in Japan.
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Affiliation(s)
- Satoru Taguchi
- Department of Urology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Hiroshi Fukuhara
- Department of Urology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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May V, Berchtold S, Berger A, Venturelli S, Burkard M, Leischner C, Malek NP, Lauer UM. Chemovirotherapy for pancreatic cancer: Gemcitabine plus oncolytic measles vaccine virus. Oncol Lett 2019; 18:5534-5542. [PMID: 31612061 DOI: 10.3892/ol.2019.10901] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 03/19/2019] [Indexed: 12/11/2022] Open
Abstract
Oncolytic virotherapy with vaccine viruses employs replicative vectors, which quite selectively infect tumor cells leading to massive virus replication followed by subsequent profound tumor cell death (oncolysis). Measles vaccine virus (MeV) has already shown great oncolytic activity against different types of cancers, including pancreatic cancer. Gemcitabine is a first line chemotherapeutic drug used for pancreatic cancer in palliative treatment plans. Furthermore, this drug can be used to induce senescence, a permanent cell cycle arrest, in tumor cells. In our preclinical work, three well-characterized immortalized human pancreatic cancer cell lines were used to investigate the combinatorial effect of MeV-based virotherapy together with the chemotherapeutic compound gemcitabine. Viability assays revealed that the combination of only small amounts of MeV together with subtherapeutic concentrations of gemcitabine resulted in a tumor cell mass reduction of >50%. To further investigate the replication of the oncolytic MeV vectors under these distinct combinatorial conditions, viral growth curves were generated. As a result, viral replication was found to be only slightly diminished in the presence of gemcitabine. As gemcitabine induces senescence, the effect of MeV on that phenomenon was explored using a senescence-associated β-galactosidase assay. Notably, gemcitabine-induced tumor cell senescence was not impaired by MeV. Accordingly, the chemovirotherapeutic combination of gemcitabine plus oncolytic MeV constitutes a novel therapeutic option for advanced pancreatic carcinoma that is characterized by the mutual improvement of the effectiveness of each therapeutic component.
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Affiliation(s)
- Verena May
- Department of Internal Medicine I (Gastroenterology, Gastroenterologic Oncology, Hepatology, Infectiology and Geriatric Medicine), University Hospital Tuebingen, D-72076 Tuebingen, Germany
| | - Susanne Berchtold
- Department of Internal Medicine VIII (Medical Oncology and Pneumology), University Hospital Tuebingen, D-72076 Tuebingen, Germany.,German Cancer Consortium (DKTK), DKFZ Partner Site Tuebingen, Interfaculty Institute of Biology, D-72076 Tuebingen, Germany
| | - Alexander Berger
- Boehringer Ingelheim Pharma GmbH and Co. KG, D-88397 Biberach/Riss, Germany
| | - Sascha Venturelli
- Department of Vegetative and Clinical Physiology, University Hospital Tuebingen, D-72076 Tuebingen, Germany
| | - Markus Burkard
- Department of Vegetative and Clinical Physiology, University Hospital Tuebingen, D-72076 Tuebingen, Germany
| | - Christian Leischner
- Department of Vegetative and Clinical Physiology, University Hospital Tuebingen, D-72076 Tuebingen, Germany
| | - Nisar P Malek
- Department of Internal Medicine I (Gastroenterology, Gastroenterologic Oncology, Hepatology, Infectiology and Geriatric Medicine), University Hospital Tuebingen, D-72076 Tuebingen, Germany
| | - Ulrich M Lauer
- Department of Internal Medicine VIII (Medical Oncology and Pneumology), University Hospital Tuebingen, D-72076 Tuebingen, Germany.,German Cancer Consortium (DKTK), DKFZ Partner Site Tuebingen, Interfaculty Institute of Biology, D-72076 Tuebingen, Germany
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Wu Z, Ichinose T, Naoe Y, Matsumura S, Villalobos IB, Eissa IR, Yamada S, Miyajima N, Morimoto D, Mukoyama N, Nishikawa Y, Koide Y, Kodera Y, Tanaka M, Kasuya H. Combination of Cetuximab and Oncolytic Virus Canerpaturev Synergistically Inhibits Human Colorectal Cancer Growth. MOLECULAR THERAPY-ONCOLYTICS 2019; 13:107-115. [PMID: 31193737 PMCID: PMC6539424 DOI: 10.1016/j.omto.2019.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 04/24/2019] [Indexed: 12/28/2022]
Abstract
The naturally occurring oncolytic herpes simplex virus canerpaturev (C-REV), formerly HF10, proved its therapeutic efficacy and safety in multiple clinical trials against melanoma, pancreatic, breast, and head and neck cancers. Meanwhile, patients with colorectal cancer, which has increased in prevalence in recent decades, continue to have poor prognosis and morbidity. Combination therapy has better response rates than monotherapy. Hence, we investigated the antitumor efficacy of cetuximab, a widely used anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and C-REV, either alone or in combination, in vitro and in an in vivo human colorectal xenograft model. In human colorectal cancer cell lines with different levels of EGFR expression (HT-29, WiDr, and CW2), C-REV exhibited cytotoxic effects in a time- and dose-dependent manner, irrespective of EGFR expression. Moreover, cetuximab had no effect on viral replication in vitro. Combining cetuximab and C-REV induced a synergistic antitumor effect in HT-29 tumor xenograft models by promoting the distribution of C-REV throughout the tumor and suppressing angiogenesis. Application of cetuximab prior to C-REV yielded better tumor regression than administration of the drug after the virus. Thus, cetuximab represents an ideal virus-associated agent for antitumor therapy, and combination therapy represents a promising antitumor strategy for human colorectal cancer.
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Affiliation(s)
- Zhiwen Wu
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Toru Ichinose
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Yoshinori Naoe
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Shigeru Matsumura
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Itzel Bustos Villalobos
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Ibrahim Ragab Eissa
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Suguru Yamada
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Noriyuki Miyajima
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Daishi Morimoto
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Nobuaki Mukoyama
- Otorhinolaryngology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Yoko Nishikawa
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Yusuke Koide
- Otorhinolaryngology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Yasuhiro Kodera
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
| | - Maki Tanaka
- Takara Bio Inc., 7-4-38, Nojihigashi, Kusatsu 525-0058, Shiga, Japan
| | - Hideki Kasuya
- Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
- Cancer Immune Therapy Research Center, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan
- Corresponding author: Hideki Kasuya, MD, PhD, FACS, Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan.
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Jiang J, Zhou H, Ni C, Hu X, Mou Y, Huang D, Yang L. Immunotherapy in pancreatic cancer: New hope or mission impossible? Cancer Lett 2019; 445:57-64. [DOI: 10.1016/j.canlet.2018.10.045] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 09/29/2018] [Accepted: 10/10/2018] [Indexed: 12/17/2022]
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45
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Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model. Oncogene 2019; 38:4467-4479. [PMID: 30755732 DOI: 10.1038/s41388-019-0737-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 01/17/2019] [Accepted: 01/17/2019] [Indexed: 01/20/2023]
Abstract
Oncolytic herpes simplex viruses are proving to be effective in clinical trials against a number of cancers. Here, R-115, an oncolytic herpes simplex virus retargeted to human erbB-2, fully virulent in its target cells, and armed with murine interleukin-12 was evaluated in a murine model of glioblastoma. We show that a single R-115 injection in established tumors resulted, in about 30% of animals, in the complete eradication of the tumor, otherwise invariably lethal. The treatment also induced a significant improvement in the overall median survival time of mice and a resistance to recurrence from the same neoplasia. Such a high degree of protection was unprecedented; it was not observed before following treatments with the commonly used, mutated/attenuated oncolytic viruses. This is the first study providing the evidence of benefits offered by a fully virulent, retargeted, and armed herpes simplex virus in the treatment of glioblastoma and paves the way for clinical translation.
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LaRocca CJ, Warner SG. A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer. Biomedicines 2018; 6:biomedicines6040104. [PMID: 30400571 PMCID: PMC6316500 DOI: 10.3390/biomedicines6040104] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D's ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer.
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Affiliation(s)
| | - Susanne G Warner
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA.
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47
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Kamimura K, Yokoo T, Terai S. Gene Therapy for Pancreatic Diseases: Current Status. Int J Mol Sci 2018; 19:3415. [PMID: 30384450 PMCID: PMC6275054 DOI: 10.3390/ijms19113415] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/22/2018] [Accepted: 10/29/2018] [Indexed: 12/12/2022] Open
Abstract
The pancreas is a key organ involved in digestion and endocrine functions in the body. The major diseases of the pancreas include pancreatitis, pancreatic cancer, cystic diseases, pancreatic divisum, islet cell tumors, endocrine tumors, diabetes mellitus, and pancreatic pain induced by these diseases. While various therapeutic methodologies have been established to date, however, the improvement of conventional treatments and establishment of novel therapies are essential to improve the efficacy. For example, conventional therapeutic options, including chemotherapy, are not effective against pancreatic cancer, and despite improvements in the last decade, the mortality rate has not declined and is estimated to become the second cause of cancer-related deaths by 2030. Therefore, continuous efforts focus on the development of novel therapeutic options. In this review, we will summarize the progress toward the development of gene therapies for pancreatic diseases, with an emphasis on recent preclinical studies and clinical trials. We aim to identify new areas for improvement of the current methodologies and new strategies that will lead to safe and effective gene therapeutic approaches in pancreatic diseases.
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Affiliation(s)
- Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Aasahimachi-Dori, Chuo-Ku, Niigata 951-8510, Japan.
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Aasahimachi-Dori, Chuo-Ku, Niigata 951-8510, Japan.
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Aasahimachi-Dori, Chuo-Ku, Niigata 951-8510, Japan.
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The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Cancers (Basel) 2018; 10:cancers10100356. [PMID: 30261620 PMCID: PMC6210336 DOI: 10.3390/cancers10100356] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev—C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.
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Abstract
PURPOSE OF REVIEW Oncolytic virotherapy is a new approach to the treatment of cancer and its success in the treatment of melanoma represents a breakthrough in cancer therapeutics. This paper provides a review of the current literature on the use of oncolytic viruses (OVs) in the treatment of melanoma. RECENT FINDINGS Talimogene laherparepvec (T-VEC) is the first OV approved for the treatment of melanoma and presents new challenges as it enters the clinical setting. Several other OVs are at various stages of clinical and pre-clinical development for the treatment of melanoma. Reports from phase Ib-III clinical trials combining T-VEC with checkpoint blockade are encouraging and demonstrate potential added benefit of combination immunotherapy. OVs have recently emerged as a standard treatment option for patients with advanced melanoma. Several OVs and therapeutic combinations are in development. Immunooncolytic virotherapy combined with immune checkpoint inhibitors is promising for the treatment of advanced melanoma.
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Leoni V, Vannini A, Gatta V, Rambaldi J, Sanapo M, Barboni C, Zaghini A, Nanni P, Lollini PL, Casiraghi C, Campadelli-Fiume G. A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. PLoS Pathog 2018; 14:e1007209. [PMID: 30080893 PMCID: PMC6095629 DOI: 10.1371/journal.ppat.1007209] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 08/16/2018] [Accepted: 07/11/2018] [Indexed: 12/12/2022] Open
Abstract
Oncolytic herpes simplex viruses (oHSVs) showed efficacy in clinical trials and practice. Most of them gain cancer-specificity from deletions/mutations in genes that counteract the host response, and grow selectively in cancer cells defective in anti-viral response. Because of the deletions/mutations, they are frequently attenuated or over-attenuated. We developed next-generation oHSVs, which carry no deletion/mutation, gain cancer-specificity from specific retargeting to tumor cell receptors-e.g. HER2 (human epidermal growth factor receptor 2)-hence are fully-virulent in the targeted cancer cells. The type of immunotherapy they elicit was not predictable, since non-attenuated HSVs induce and then dampen the innate response, whereas deleted/attenuated viruses fail to contrast it, and since the retargeted oHSVs replicate efficiently in tumor cells, but spare other cells in the tumor. We report on the first efficacy study of HER2-retargeted, fully-virulent oHSVs in immunocompetent mice. Their safety profile was very high. Both the unarmed R-LM113 and the IL-12-armed R-115 inhibited the growth of the primary HER2-Lewis lung carcinoma-1 (HER2-LLC1) tumor, R-115 being constantly more efficacious. All the mice that did not die because of the primary treated tumors, were protected from the growth of contralateral untreated tumors. The long-term survivors were protected from a second contralateral tumor, providing additional evidence for an abscopal immunotherapeutic effect. Analysis of the local response highlighted that particularly R-115 unleashed the immunosuppressive tumor microenvironment, i.e. induced immunomodulatory cytokines, including IFNγ, T-bet which promoted Th1 polarization. Some of the tumor infiltrating cells, e.g. CD4+, CD335+ cells were increased in the tumors of all responders mice, irrespective of which virus was employed, whereas CD8+, Foxp3+, CD141+ were increased and CD11b+ cells were decreased preferentially in R-115-treated mice. The durable response included a breakage of tolerance towards both HER2 and the wt tumor cells, and underscored a systemic immunotherapeutic vaccine response.
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Affiliation(s)
- Valerio Leoni
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Andrea Vannini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Valentina Gatta
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Julie Rambaldi
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Mara Sanapo
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Catia Barboni
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Anna Zaghini
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Patrizia Nanni
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Pier-Luigi Lollini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Costanza Casiraghi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Gabriella Campadelli-Fiume
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
- * E-mail:
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