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Varela ML, Comba A, Faisal SM, Argento A, Peña Aguelo JA, Candolfi M, Castro MG, Lowenstein PR. Cell and gene therapy in neuro-oncology. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:297-315. [PMID: 39341660 PMCID: PMC11441620 DOI: 10.1016/b978-0-323-90120-8.00009-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
The majority of primary brain tumors are gliomas, among which glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 18-24 months, and despite extensive research it remains incurable, thus novel therapies are urgently needed. The current standard of care is a combination of surgery, radiation, and chemotherapy, but still remains ineffective due to the invasive nature and high recurrence of gliomas. Gene therapy is a versatile treatment strategy investigated for multiple tumor types including GBM. In gene therapy, a variety of vectors are employed to deliver genes designed for different antitumoral effects. Also, over the past decades, stem cell biology has provided a new approach to cancer therapies. Stem cells can be used as regenerative medicine, therapeutic carriers, drug targeting, and generation of immune cells. Stem cell-based therapy allows targeted therapy that spares healthy brain tissue as well as establishes a long-term antitumor response by stimulating the immune system and delivering prodrug, metabolizing genes, or even oncolytic viruses. This chapter describes the latest developments and the current trends in gene and cell-based therapy against GBM from both preclinical and clinical perspectives, including different gene therapy delivery systems, molecular targets, and stem cell therapies.
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Affiliation(s)
- Maria Luisa Varela
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Comba
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Syed M Faisal
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Anna Argento
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Jorge A Peña Aguelo
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marianela Candolfi
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Maria G Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Pedro R Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States.
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Varela ML, Comba A, Faisal SM, Argento A, Franson A, Barissi MN, Sachdev S, Castro MG, Lowenstein PR. Gene Therapy for High Grade Glioma: The Clinical Experience. Expert Opin Biol Ther 2023; 23:145-161. [PMID: 36510843 PMCID: PMC9998375 DOI: 10.1080/14712598.2022.2157718] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of ~18 months. The standard of care (SOC) is maximal safe surgical resection, and radiation therapy with concurrent and adjuvant temozolomide. This protocol remains unchanged since 2005, even though HGG median survival has marginally improved. AREAS COVERED Gene therapy was developed as a promising approach to treat HGG. Here, we review completed and ongoing clinical trials employing viral and non-viral vectors for adult and pediatric HGG, as well as the key supporting preclinical data. EXPERT OPINION These therapies have proven safe, and pre- and post-treatment tissue analyses demonstrated tumor cell lysis, increased immune cell infiltration, and increased systemic immune function. Although viral therapy in clinical trials has not yet significantly extended the survival of HGG, promising strategies are being tested. Oncolytic HSV vectors have shown promising results for both adult and pediatric HGG. A recently published study demonstrated that HG47Δ improved survival in recurrent HGG. Likewise, PVSRIPO has shown survival improvement compared to historical controls. It is likely that further analysis of these trials will stimulate the development of new administration protocols, and new therapeutic combinations that will improve HGG prognosis.
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Affiliation(s)
- Maria Luisa Varela
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Comba
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Syed M Faisal
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Anna Argento
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Andrea Franson
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Marcus N Barissi
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Sean Sachdev
- Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL USA
| | - Maria G Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Pedro R Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, United States
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Alekseenko I, Kuzmich A, Kondratyeva L, Kondratieva S, Pleshkan V, Sverdlov E. Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement. Int J Mol Sci 2021; 22:ijms22179376. [PMID: 34502287 PMCID: PMC8430744 DOI: 10.3390/ijms22179376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 11/16/2022] Open
Abstract
Gene-directed enzyme prodrug gene therapy (GDEPT) theoretically represents a useful method to carry out chemotherapy for cancer with minimal side effects through the formation of a chemotherapeutic agent inside cancer cells. However, despite great efforts, promising preliminary results, and a long period of time (over 25 years) since the first mention of this method, GDEPT has not yet reached the clinic. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. The advent of checkpoint immunotherapy has yielded new highly promising avenues of study in cancer therapy. For such therapy, it seems reasonable to use combinations of different immunomodulators alongside traditional methods, such as chemotherapy and radiotherapy, as well as GDEPT. In this review, we focused on non-viral gene immunotherapy systems combining the intratumoral production of toxins diffused by GDEPT and immunomodulatory molecules. Special attention was paid to the applications and mechanisms of action of the granulocyte-macrophage colony-stimulating factor (GM–CSF), a cytokine that is widely used but shows contradictory effects. Another method to enhance the formation of stable immune responses in a tumor, the use of danger signals, is also discussed. The process of dying from GDEPT cancer cells initiates danger signaling by releasing damage-associated molecular patterns (DAMPs) that exert immature dendritic cells by increasing antigen uptake, maturation, and antigen presentation to cytotoxic T-lymphocytes. We hypothesized that the combined action of this danger signal and GM–CSF issued from the same dying cancer cell within a limited space would focus on a limited pool of immature dendritic cells, thus acting synergistically and enhancing their maturation and cytotoxic T-lymphocyte attraction potential. We also discuss the problem of enhancing the cancer specificity of the combined GDEPT–GM–CSF–danger signal system by means of artificial cancer specific promoters or a modified delivery system.
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Affiliation(s)
- Irina Alekseenko
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
- Institute of Oncogynecology and Mammology, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Correspondence: (I.A.); (E.S.)
| | - Alexey Kuzmich
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Liya Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Sofia Kondratieva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Victor Pleshkan
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia; (L.K.); (S.K.)
| | - Eugene Sverdlov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (A.K.); (V.P.)
- Correspondence: (I.A.); (E.S.)
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Banerjee K, Núñez FJ, Haase S, McClellan BL, Faisal SM, Carney SV, Yu J, Alghamri MS, Asad AS, Candia AJN, Varela ML, Candolfi M, Lowenstein PR, Castro MG. Current Approaches for Glioma Gene Therapy and Virotherapy. Front Mol Neurosci 2021; 14:621831. [PMID: 33790740 PMCID: PMC8006286 DOI: 10.3389/fnmol.2021.621831] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 02/16/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.
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Affiliation(s)
- Kaushik Banerjee
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Felipe J. Núñez
- Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir, Buenos Aires, Argentina
| | - Santiago Haase
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Brandon L. McClellan
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Immunology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Syed M. Faisal
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Stephen V. Carney
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Cancer Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Jin Yu
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Mahmoud S. Alghamri
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Antonela S. Asad
- Departamento de Biología e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alejandro J. Nicola Candia
- Departamento de Biología e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Maria Luisa Varela
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Marianela Candolfi
- Departamento de Biología e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Pedro R. Lowenstein
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Maria G. Castro
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
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Hemmati S, Keshavarz-Fathi M, Razi S, Rezaei N. Gene Therapy and Genetic Vaccines. CANCER IMMUNOLOGY 2021:129-142. [DOI: 10.1007/978-3-030-50287-4_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Dogrammatzis C, Waisner H, Kalamvoki M. "Non-Essential" Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review. Viruses 2020; 13:E17. [PMID: 33374862 PMCID: PMC7824580 DOI: 10.3390/v13010017] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/19/2022] Open
Abstract
Viruses encode for structural proteins that participate in virion formation and include capsid and envelope proteins. In addition, viruses encode for an array of non-structural accessory proteins important for replication, spread, and immune evasion in the host and are often linked to virus pathogenesis. Most virus accessory proteins are non-essential for growth in cell culture because of the simplicity of the infection barriers or because they have roles only during a state of the infection that does not exist in cell cultures (i.e., tissue-specific functions), or finally because host factors in cell culture can complement their absence. For these reasons, the study of most nonessential viral factors is more complex and requires development of suitable cell culture systems and in vivo models. Approximately half of the proteins encoded by the herpes simplex virus 1 (HSV-1) genome have been classified as non-essential. These proteins have essential roles in vivo in counteracting antiviral responses, facilitating the spread of the virus from the sites of initial infection to the peripheral nervous system, where it establishes lifelong reservoirs, virus pathogenesis, and other regulatory roles during infection. Understanding the functions of the non-essential proteins of herpesviruses is important to understand mechanisms of viral pathogenesis but also to harness properties of these viruses for therapeutic purposes. Here, we have provided a comprehensive summary of the functions of HSV-1 non-essential proteins.
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Affiliation(s)
| | | | - Maria Kalamvoki
- Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, KS 66160, USA; (C.D.); (H.W.)
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Manikandan C, Kaushik A, Sen D. Viral vector: potential therapeutic for glioblastoma multiforme. Cancer Gene Ther 2019; 27:270-279. [PMID: 31316136 DOI: 10.1038/s41417-019-0124-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 06/29/2019] [Indexed: 02/06/2023]
Abstract
Glioblastoma multiforme is a highly malignant primary brain tumour found in adults and is highlighted as the most devastating among all the other grades of glioma. Well-established standard treatment methods, such as chemotherapy, radiation and surgery, have resulted in modest improvement in the survival of patients. Hence, the arduous search for novel treatments backed by advancements in molecular biology still persists. Glioblastoma has many distinctive characteristics, which makes it a potential candidate for gene therapy. Gene therapy involves the delivery of genetic material of therapeutic use into tumour cells, which produces a specific antitumour response. Moreover, viruses stimulate a vigorous cytotoxic effect, they are easily modifiable and the inherent property of horizontal transfer of genetic material makes them valuable tools for genetic engineering. In this review, we have enlisted the various viral vectors employed in gene therapy for glioblastoma.
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Affiliation(s)
- Ceera Manikandan
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT) University, Vellore, Tamil Nadu, 632014, India
| | - Akshita Kaushik
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT) University, Vellore, Tamil Nadu, 632014, India
| | - Dwaipayan Sen
- Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT) University, Vellore, Tamil Nadu, 632014, India.
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Abstract
Introduction: Prodrugs have been used to improve the selectivity and efficacy of cancer therapy by targeting unique abnormal markers that are overexpressed by cancer cells and are absent in normal tissues. In this context, different strategies have been exploited and new ones are being developed each year. Areas covered: In this review, an integrated view of the potential use of prodrugs in targeted cancer therapy is provided. Passive and active strategies are discussed in light of the advantages of each one and some successful examples are provided, as well as the clinical status of several prodrugs. Among them, antibody-drug conjugates (ADCs) are the most commonly used. However, several drawbacks, including limited prodrug uptake, poor pharmacokinetics, immunogenicity problems, difficulties in selective targeting and gene expression, and optimized bystander effects limit their clinical applications. Expert opinion: Despite the efforts of different companies and research groups, several drawbacks, such as the lack of relevant in vivo models, complexity of the human metabolism, and economic limitations, have hampered the development of new prodrugs for targeted cancer therapy. As a result, we believe that the combination of prodrugs with cancer nanotechnology and other newly developed approaches, such as aptamer-conjugated nanomaterials, are efficient strategies.
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Affiliation(s)
- Carla Souza
- a Center of Nanotechnology and Tissue Engineering, Department of Chemistry , School of Philosophy, Sciences and Letters of Ribeirão Preto- USP , Ribeirão Preto , Brazil
| | - Diogo Silva Pellosi
- b Department of Chemistry, Laboratory of Hybrid Materials , Federal University of São Paulo - UNIFESP , Diadema , Brazil
| | - Antonio Claudio Tedesco
- a Center of Nanotechnology and Tissue Engineering, Department of Chemistry , School of Philosophy, Sciences and Letters of Ribeirão Preto- USP , Ribeirão Preto , Brazil
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Xie Y, Wu L, Wang M, Cheng A, Yang Q, Wu Y, Jia R, Zhu D, Zhao X, Chen S, Liu M, Zhang S, Wang Y, Xu Z, Chen Z, Zhu L, Luo Q, Liu Y, Yu Y, Zhang L, Chen X. Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets. Front Microbiol 2019; 10:941. [PMID: 31134006 PMCID: PMC6517553 DOI: 10.3389/fmicb.2019.00941] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 04/12/2019] [Indexed: 12/20/2022] Open
Abstract
Alpha-herpesvirus thymidine kinase (TK) genes are virulence-related genes and are nonessential for viral replication; they are often preferred target genes for the construction of gene-deleted attenuated vaccines and genetically engineered vectors for inserting and expressing foreign genes. The enzymes encoded by TK genes are key kinases in the nucleoside salvage pathway and have significant substrate diversity, especially the herpes simplex virus 1 (HSV-1) TK enzyme, which phosphorylates four nucleosides and various nucleoside analogues. Hence, the HSV-1 TK gene is exploited for the treatment of viral infections, as a suicide gene in antitumor therapy, and even for the regulation of stem cell transplantation and treatment of parasitic infection. This review introduces the effects of α-herpesvirus TK genes on viral virulence and infection in the host and classifies and summarizes the current main application domains and potential uses of these genes. In particular, mechanisms of action, clinical limitations, and antiviral and antitumor therapy development strategies are discussed.
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Affiliation(s)
- Ying Xie
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Liping Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - XinXin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yin Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Zhengli Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qihui Luo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoyue Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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Liu X, Xu J, Wang S, Yu X, Kou B, Chai M, Zang Y, Chen D. Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo. Int J Oncol 2017; 51:1291-1299. [PMID: 28902369 DOI: 10.3892/ijo.2017.4105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/26/2017] [Indexed: 11/06/2022] Open
Abstract
The present study was designed to investigate the synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 (Aspp2-ad) and oxaliplatin via p53-independent pathway in vitro and in vivo. After being treated with Aspp2-ad and/or oxaliplatin for 24-48 h, HepG2P53-/- and Hep3B cells showed a significant growth inhibition compared with vehicle control. Combination group showed a synergetic effect, the inhibitory rates were all above 80% at 48 h point in HepG2P53-/- and Hep3B cells. The apoptotic cell numbers of Aspp2-ad and/or oxaliplatin treatment groups were increased remarkably, especially for the combined therapy group in the liver cancer cells. The Hep3B xenograft experiment also showed similar inhibition of Aspp2-ad and/or oxaliplatin to the in vitro experiment. H&E results showed that combination group had the least mitotic indexes and the most necrosis. The immunohistochemistry results showed that PCNA, CD31 expression decreased greatly in treatment groups. These results suggested that Aspp2-ad might inhibit proliferation and vascular growth of hepatocarcinoma. Aspp2 induced apoptosis protein expression in Aspp2-ad and combination groups, the Aspp2, Bax and activation of caspase-3 expression increased greatly both in vitro and in vivo. But interestingly, the autophagy proteins showed different responses not only in HepG2P53-/- and Hep3B cells but also in vitro and in vivo. We found that Aspp2-ad downregulated the p-ERK, p-STAT3 expression, the synergistic effects were observed in combination group, while there was not response of mTOR to Aspp2-ad. In conclusion, Aspp2-ad, in P53-independent manner, regulated ERK and STAT3 signal moleculars to inhibit hepatocarcinoma in coordination with oxaliplatin by influencing the protein expression of proliferation, apoptosis, autophagy and vascular growth. Aspp2-ad has the potential to be developed in gene therapy for HCC, especially for P53 deletion or mutation in HCC.
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Affiliation(s)
- Xiaoni Liu
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Jianji Xu
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Shuang Wang
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiaoxiao Yu
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Boxin Kou
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Mengyin Chai
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Yunjin Zang
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Dexi Chen
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
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11
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Progress and problems with the use of suicide genes for targeted cancer therapy. Adv Drug Deliv Rev 2016; 99:113-128. [PMID: 26004498 DOI: 10.1016/j.addr.2015.05.009] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 02/19/2015] [Accepted: 05/14/2015] [Indexed: 12/16/2022]
Abstract
Among various gene therapy methods for cancer, suicide gene therapy attracts a special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. As a result, therapeutic index can be increased significantly by introducing high concentrations of cytotoxic molecules to the tumor environment while minimizing impact on normal tissues. Despite significant success at the preclinical level, no cancer suicide gene therapy protocol has delivered the desirable clinical significance yet. This review gives a critical look at the six main enzyme/prodrug systems that are used in suicide gene therapy of cancer and familiarizes readers with the state-of-the-art research and practices in this field. For each enzyme/prodrug system, the mechanisms of action, protein engineering strategies to enhance enzyme stability/affinity and chemical modification techniques to increase prodrug kinetics and potency are discussed. In each category, major clinical trials that have been performed in the past decade with each enzyme/prodrug system are discussed to highlight the progress to date. Finally, shortcomings are underlined and areas that need improvement in order to produce clinical significance are delineated.
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12
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Nouri FS, Wang X, Hatefi A. Genetically engineered theranostic mesenchymal stem cells for the evaluation of the anticancer efficacy of enzyme/prodrug systems. J Control Release 2015; 200:179-87. [PMID: 25575867 DOI: 10.1016/j.jconrel.2015.01.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 12/30/2014] [Accepted: 01/03/2015] [Indexed: 12/27/2022]
Abstract
Over the past decade, various enzyme/prodrug systems such as thymidine kinase/ganciclovir (TK/GCV), yeast cytosine deaminase/5-fluorocytosine (yCD/5-FC) and nitroreductase/CB1954 (NTR/CB1954) have been used for stem cell mediated suicide gene therapy of cancer. Yet, no study has been conducted to compare and demonstrate the advantages and disadvantages of using one system over another. Knowing that each enzyme/prodrug system has its own strengths and weaknesses, we utilized mesenchymal stem cells (MSCs) as a medium to perform for the first time a comparative study that illustrated the impact of subtle differences among these systems on the therapeutic outcome. For therapeutic purposes, we first genetically modified MSCs to stably express a panel of four suicide genes including TK (TK007 and TK(SR39) mutants), yeast cytosine deaminase:uracil phosphoribosyltransferase (yCD:UPRT) and nitroreductase (NTR). Then, we evaluated the anticancer efficacies of the genetically engineered MSCs in vitro and in vivo by using SKOV3 cell line which is sensitive to all four enzyme/prodrug systems. In addition, all MSCs were engineered to stably express luciferase gene making them suitable for quantitative imaging and dose-response relationship studies in animals. Considering the limitations imposed by the prodrugs' bystander effects, our findings show that yCD:UPRT/5-FC is the most effective enzyme/prodrug system among the ones tested. Our findings also demonstrate that theranostic MSCs are a reliable medium for the side-by-side evaluation and screening of the enzyme/prodrug systems at the preclinical level. The results of this study could help scientists who utilize cell-based, non-viral or viral vectors for suicide gene therapy of cancer make more informed decisions when choosing enzyme/prodrug systems.
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Affiliation(s)
- Faranak Salman Nouri
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Xing Wang
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Arash Hatefi
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
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13
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Zhao F, Tian J, An L, Yang K. Prognostic utility of gene therapy with herpes simplex virus thymidine kinase for patients with high-grade malignant gliomas: a systematic review and meta analysis. J Neurooncol 2014; 118:239-246. [PMID: 24756350 DOI: 10.1007/s11060-014-1444-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 04/09/2014] [Indexed: 11/24/2022]
Abstract
The aim of this study was to assess the effectiveness of adding viral vector-mediated gene therapy with herpes simplex virus thymidine kinase (HSV-tk) to standard treatment, in comparison with standard treatment alone to treat patients with high-grade gliomas (HGGs). A literature search of the databases PubMed, Embase, the Cochrane Library, Web of Science, and Chinese biomedicine was performed to identify eligible studies. Three randomized controlled trials (involving a total of 532 patients) were included in this systematic review. A meta-analysis of included studies demonstrated a significant increase in median survival time (MST) in patients who were treated with HSV-tk gene therapy (mean deviation 0.59, 95% CI: 0.41-0.76, p < 0.0001). The results of pooled analysis for different patient groups show that overall survival (OS) for all HGG patients was improved by adding gene therapy [hazard ratio (HR) = 0.91, 95% CI: 0.74-1.13, p = 0.42], while a different result was seen for glioblastoma multiforme (GBM) patients (HR = 1.06, 95% CI: 0.80-1.41, p = 0.70). Furthermore, the combined results for tumor progression implied that standard therapy was superior to gene therapy [odds ratio (OR) = 1.31, p = 0.09]; yet differences in HR and OR between experimental groups and control groups had no statistical significance (p > 0.05). Based on the best available evidence, it appears that adding gene therapy with HSV-tk has some effect in treating HGG patients, especially with respect to MST. However, neither the pooled analysis of OS, nor the combined analysis of tumor progress indicates any significant advantage to adding gene therapy compared with standard treatment alone. More prospective studies are needed to draw solid conclusions about whether gene therapy has significant prognostic advantage.
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Affiliation(s)
- Fei Zhao
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Institution of Integrated Traditional Chinese with Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,School of Medicine, Northwest University of Nationality, Lanzhou, China
| | - Jinhui Tian
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Lifeng An
- School of Medicine, Northwest University of Nationality, Lanzhou, China
| | - Kehu Yang
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China. .,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.
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Stopschinski BE, Beier CP, Beier D. Glioblastoma cancer stem cells – From concept to clinical application. Cancer Lett 2013; 338:32-40. [DOI: 10.1016/j.canlet.2012.05.033] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 05/26/2012] [Accepted: 05/28/2012] [Indexed: 01/04/2023]
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Current status of local therapy in malignant gliomas--a clinical review of three selected approaches. Pharmacol Ther 2013; 139:341-58. [PMID: 23694764 DOI: 10.1016/j.pharmthera.2013.05.003] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Accepted: 05/12/2013] [Indexed: 12/21/2022]
Abstract
Malignant gliomas are the most frequently occurring, devastating primary brain tumors, and are coupled with a poor survival rate. Despite the fact that complete neurosurgical resection of these tumors is impossible in consideration of their infiltrating nature, surgical resection followed by adjuvant therapeutics, including radiation therapy and chemotherapy, is still the current standard therapy. Systemic chemotherapy is restricted by the blood-brain barrier, while methods of local delivery, such as with drug-impregnated wafers, convection-enhanced drug delivery, or direct perilesional injections, present attractive ways to circumvent these barriers. These methods are promising ways for direct delivery of either standard chemotherapeutic or new anti-cancer agents. Several clinical trials showed controversial results relating to the influence of a local delivery of chemotherapy on the survival of patients with both recurrent and newly diagnosed malignant gliomas. Our article will review the development of the drug-impregnated release, as well as convection-enhanced delivery and the direct injection into brain tissue, which has been used predominantly in gene-therapy trials. Further, it will focus on the use of convection-enhanced delivery in the treatment of patients with malignant gliomas, placing special emphasis on potential shortcomings in past clinical trials. Although there is a strong need for new or additional therapeutic strategies in the treatment of malignant gliomas, and although local delivery of chemotherapy in those tumors might be a powerful tool, local therapy is used only sporadically nowadays. Thus, we have to learn from our mistakes in the past and we strongly encourage future developments in this field.
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Current status of gene therapy for brain tumors. Transl Res 2013; 161:339-54. [PMID: 23246627 PMCID: PMC3733107 DOI: 10.1016/j.trsl.2012.11.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 11/14/2012] [Accepted: 11/16/2012] [Indexed: 01/06/2023]
Abstract
Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.
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17
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Current world literature. Curr Opin Pediatr 2012; 24:770-9. [PMID: 23146873 DOI: 10.1097/mop.0b013e32835af8de] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Finocchiaro LME, Glikin GC. Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma: 9 years of follow-up. Cancer Gene Ther 2012; 19:852-61. [PMID: 23059870 DOI: 10.1038/cgt.2012.72] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
We present here the updated results after 9 years of the beginning of a trial on canine patients with malignant melanoma. This surgery adjuvant approach combined local suicide gene therapy with a subcutaneous vaccine composed by tumor cells extracts and xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. Toxicity was absent or minimal in all patients (0≤VCOG-CTCAE grade≤1). With respect to surgery-treated controls (ST), the complete surgery (CS) arm of this combined treatment (CT) significantly increased the fraction of local disease-free patients from 13 to 81% and distant metastases free from 32 to 84%. Even though less effective than the CS arm, the partial surgery (PS) arm of this CT was significantly better controlling the disease than only surgery (14% while PS-ST: 0%, P<0.01 and CS-ST: 5%, P<0.05). In addition, CT produced a significant sevenfold (CS) and threefold (PS) increase in overall survival. The CS-CT arm significantly improved both CS-ST metastasis-free- and melanoma overall survival from 99 days (respective ranges: 11-563 and 10-568) to >2848 days (81-2848 and 35-2848). Thus, more of 50% of our CT patients died of melanoma unrelated causes, transforming a lethal disease into a chronic one. Finally, surgery adjuvant CT delayed or prevented post-surgical recurrence and distant metastasis, significantly improved disease-free and overall survival maintaining the quality of life. Long-term safety and efficacy of this treatment are supported by the high number of CT patients (283) and extensive follow-up (>9 years). The successful clinical outcome encourages the further translation of similar approaches to human gene therapy trials.
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Affiliation(s)
- L M E Finocchiaro
- Unidad de Transferencia Genética, Instituto de Oncología Ángel H. Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina
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Wirth T. A short perspective on gene therapy: Clinical experience on gene therapy of gliomablastoma multiforme. World J Exp Med 2011; 1:10-6. [PMID: 24520527 PMCID: PMC3905579 DOI: 10.5493/wjem.v1.i1.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Revised: 12/12/2011] [Accepted: 12/16/2011] [Indexed: 02/06/2023] Open
Abstract
More than two decades have passed since the first gene therapy clinical trial was conducted. During this time, we have gained much knowledge regarding gene therapy in general, but also learned to understand the fear that persists in society. We have experienced drawbacks and successes. More than 1700 clinical trials have been conducted where gene therapy is used as a means for therapy. In the very first trial, patients with advanced melanoma were treated with tumor infiltrating lymphocytes genetically modified ex-vivo to express tumor necrosis factor. Around the same time the first gene therapy trial was conducted, the ethical aspects of performing gene therapy on humans was intensively discussed. What are the risks involved with gene therapy? Can we control the technology? What is ethically acceptable and what are the indications gene therapy can be used for? Initially, gene therapy was thought to be implemented mainly for the treatment of monogenetic diseases, such as adenosine deaminase deficiency. However, other therapeutic areas have become of interest and currently cancer is the most studied therapeutic area for gene therapy based medicines. In this review I will be giving a short introduction into gene therapy and will direct the discussion to where we should go from here. Furthermore, I will focus on the use of the Herpes simplex virus-thymidine kinase for gene therapy of malignant gliomas and highlight the efficacy of gene therapy for the treatment of malignant gliomas, but other strategies will also be mentioned.
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Affiliation(s)
- Thomas Wirth
- Thomas Wirth, AI Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Neulaniementie 2, FIN-70211 Kuopio, Finland
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Cebrián V, Martín-Saavedra F, Yagüe C, Arruebo M, Santamaría J, Vilaboa N. Size-dependent transfection efficiency of PEI-coated gold nanoparticles. Acta Biomater 2011; 7:3645-55. [PMID: 21704738 DOI: 10.1016/j.actbio.2011.06.018] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/08/2011] [Accepted: 06/09/2011] [Indexed: 11/19/2022]
Abstract
Gold nanoparticles (Au NPs) are promising vectors for gene delivery applications. In order to gain insight on the influence of particle size on cell transfection, Au NPs were combined with poly(ethylenimine) (PEI) to prepare two sets of PEI-coated Au NPs having particle-size distributions centered at about 6 nm (<10nm Au-PEI NPs) or 70 nm (<100 nm Au-PEI NPs), respectively. Au-PEI NPs were coupled to a variety of plasmids carrying reporter or suicide genes to prepare Au-PEI NPs/DNA complexes, and human osteosarcoma Saos-2 cells were used to investigate the performance of the Au-PEI NPs as transfection vectors in serum-containing media. The conjugates of DNA with both types of Au-PEI NPs were found to be negatively charged. In spite of the electrostatic repulsion that occurs between the surface of the cell and the surface of the plasmid-conjugated NPs, cell internalization was observed for both kinds of Au-PEI NPs. Cells were efficiently transfected with complexes derived from <10 nm Au-PEI NPs, but not with the <100 nm Au-PEI NPs. Large aggregates of NPs associated with DNA were found in endocytic vesicles of cells incubated with <100 nm Au-PEI NPs, while the success of the smaller Au-PEI NPs as transfection vectors was related to their lower agglomeration state inside cells and to endosomal escape of DNA.
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Affiliation(s)
- Virginia Cebrián
- Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain
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Assessment of the evolution of cancer treatment therapies. Cancers (Basel) 2011; 3:3279-330. [PMID: 24212956 PMCID: PMC3759197 DOI: 10.3390/cancers3033279] [Citation(s) in RCA: 505] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Revised: 07/07/2011] [Accepted: 08/08/2011] [Indexed: 11/16/2022] Open
Abstract
Cancer therapy has been characterized throughout history by ups and downs, not only due to the ineffectiveness of treatments and side effects, but also by hope and the reality of complete remission and cure in many cases. Within the therapeutic arsenal, alongside surgery in the case of solid tumors, are the antitumor drugs and radiation that have been the treatment of choice in some instances. In recent years, immunotherapy has become an important therapeutic alternative, and is now the first choice in many cases. Nanotechnology has recently arrived on the scene, offering nanostructures as new therapeutic alternatives for controlled drug delivery, for combining imaging and treatment, applying hyperthermia, and providing directed target therapy, among others. These therapies can be applied either alone or in combination with other components (antibodies, peptides, folic acid, etc.). In addition, gene therapy is also offering promising new methods for treatment. Here, we present a review of the evolution of cancer treatments, starting with chemotherapy, surgery, radiation and immunotherapy, and moving on to the most promising cutting-edge therapies (gene therapy and nanomedicine). We offer an historical point of view that covers the arrival of these therapies to clinical practice and the market, and the promises and challenges they present.
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