Edited by
Director, Center for Cell and Gene Therapy
Baylor College of Medicine
Houston, TX, USA
Chair, Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
SERIES EDITORS
ROBERT C. BAST, MD
Vice President for Translational Research
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
MAURIE MARKMAN, MD
Senior Vice President for Clinical Affairs
Cancer Treatment Centers of America
Clinical Professor of Medicine
Drexel University College of Medicine
Philadelphia, PA, USA
ERNEST HAWK, MD, MPH
Vice President, Division of OVP, Cancer Prevention and Population Sciences
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved
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Library of Congress Cataloging-in-Publication Data
Cancer gene therapy by viral and non-viral vectors / edited by Malcolm K. Brenner, Mien-Chie Hung.
p. ; cm. – (Translational oncology ; 4)
Includes bibliographical references and index.
ISBN 978-1-118-50162-7 (hardback)
I. Brenner, Malcolm K., 1951– editor of compilation. II. Hung, Mien-chie, editor of compilation.
[DNLM: 1. Neoplasms–therapy. 2. Genetic Therapy. 3. Genetic Vectors–therapeutic use. 4. Oncolytic Virotherapy. QZ 266]
RC268.4
616.99′4042–dc23
2013049552
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Malcolm K. Brenner, MB, BChir, PhD
Center for Cell and Gene Therapy
Baylor College of Medicine
Houston, TX, USA
John C. Burnett, PhD
Department of Molecular and Cellular Biology
Beckman Research Institute of City of Hope
Duarte, CA, USA
George A. Calin, MD, PhD
Department of Experimental Therapeutics
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Vincenzo Cerullo, PhD
Laboratory of Immunovirotherapy
Centre for Drug Research (CDR) and Division of
Pharmaceutical Bioscience
Faculty of Pharmacy
University of Helsinki
Helsinki, Finland
Laurence J.N. Cooper, MD, PhD
Division of Pediatrics
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Yue Ding, MSc
Department of Molecular and Cellular Biology
Irell and Manella Graduate School of Biological Sciences
Beckman Research Institute of City of Hope
Duarte, CA, USA
Adrian P. Gee, PhD
Center for Cell and Gene Therapy
Baylor College of Medicine
Houston, TX, USA
Bambi Grilley, RPh, RAC, CIP, CCRC, CCRP
Center for Cell and Gene Therapy
Baylor College of Medicine
Houston, TX, USA
Kilian Guse, PharmD, PhD
Cancer Gene Therapy Group
Haartman Institute
University of Helsinki
Helsinki, Finland
Akseli Hemminki MD, PhD
Cancer Gene Therapy Group
Haartman Institute
University of Helsinki
Helsinki, Finland
Jennifer L. Hsu, PhD
Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Yi-Hsin Hsu, PhD
Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Leaf Huang, PhD
Division of Molecular Pharmaceutics
Eshelman School of Pharmacy
UNC-NCSU Joint Department of Biomedical Engineering
University of North Carolina at Chapel Hill
Chapel Hill, NC, USA
Mien-Chie Hung, PhD
Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Longfei Huo, PhD
Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Chia-Wei Li, PhD
Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Hui Ling, MD, PhD
Department of Experimental Therapeutics
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Zhuyong Mei, MD
Center for Cell and Gene Therapy
Baylor College of Medicine
Houston, TX, USA
Judy S.E. Moyes, MB, BChir
Division of Pediatrics
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Amer M. Najjar, PhD
Cancer Systems Imaging
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
John Rossi, PhD
Department of Molecular and Cellular Biology
Beckman Research Institute of City of Hope
Duarte, CA, USA
Andrew B. Satterlee, BS
Division of Molecular Pharmaceutics
Eshelman School of Pharmacy
UNC-NCSU Joint Department of Biomedical Engineering
University of North Carolina at Chapel Hill
Chapel Hill, NC, USA
Markus Vähä-Koskela, PhD
Cancer Gene Therapy Group
Haartman Institute
University of Helsinki
Helsinki, Finland
Yan Wang, PhD
Department of Molecular and Cellular Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Jiehua Zhou, PhD
Department of Molecular and Cellular Biology
Beckman Research Institute of City of Hope
Duarte, CA, USA
While our knowledge of cancer at a cellular and molecular level has increased exponentially over the last decades, progress in the clinic has been more gradual, largely depending upon empirical trials using combinations of individually active anticancer drugs to treat the average patient. The challenge for the immediate future is to accelerate the pace of progress in clinical cancer care by enhancing the bidirectional interaction between laboratory and clinic. Our new understanding of human cancer biology and the heterogeneity of cancers at a molecular level must be used to identify novel targets for therapy, prevention, and detection focused on each individual. Barriers must be removed to facilitate the flow of targeted agents and fresh approaches from the laboratory to the clinic, while returning relevant human specimens, images, and data from the clinic to the laboratory for further analysis.
In this title we will provide a brief overview of our current understanding of human cancer biology that is driving interests in targeted therapy and personalized management. Further development of molecular diagnostics should facilitate earlier detection, more precise prognostication and prediction of response across the spectrum of cancer development. Targeted therapy has already had a dramatic impact on several forms of cancer and strategies are being developed to identify small groups of patients who would benefit from novel targeted drugs in combination with each other or with more conventional surgery, radiotherapy or chemotherapy. Development of personalized interventions – whether preventive or therapeutic in nature – will require multidisciplinary teams of investigators and the infrastructure to match patient samples and agents in real time.
To accelerate translational cancer research, greater alignment will be required between academic institutions, the US National Cancer Institute, the US Food and Drug Administration, foundations, pharma, and community oncologists. Ultimately, new approaches to prevention, detection, and therapy must be sustainable. In the long run, translational research and personalized management can reduce the cost of cancer care which has escalated in recent years. More accurate and specific identification of at-risk members and risk stratification will be helpful to minimize the risks of overdiagnosis and overtreatment, while maximizing the benefits of screening, early detection, and preventive intervention. Patients who would benefit most can be identified and funds saved by avoiding treatment in those whose cancers would not respond. Participation and education of community oncologists will be required, as will modification of practice patterns. For progress in the clinic to occur at an optimal pace, leaders of translational teams must envision a clear path to bring new concepts and new agents from the laboratory to the clinic, to complete pharmaceutical or biological development, to obtain regulatory approval, and to bring new strategies for detection, prevention, and treatment to patients in the community.
In a series of additional volumes regarding translational cancer research, several topics are explored in greater depth, including Biomarkers, Targeted Therapy, Immunotherapy, and this volume concerning Cancer Gene Therapy by Viral and Non-Viral Vectors. The purpose of these books has been not only to describe different strategies for particular forms of cancer, but also to identify some of the barriers to translation using different reagents or different strategies around common therapeutic or diagnostic modalities. Potential barriers include not only the need for a deeper understanding of science, methods to overcome the challenge of tumor heterogeneity, the development of targeted therapies, the availability of patients with an appropriate phenotype and genotype within a research center with the investigators, research teams, and infrastructure required for clinical/translational research and the design of novel trials, but also adequate financial support, a viable connection to diagnostic and pharmaceutical development, and a strategy for regulatory approval, as well as for dissemination in the community.
Cancer Gene Therapy by Viral and Non-Viral Vectors considers many of these areas, including the strengths and limitations of the several types of viral and non-viral delivery systems, the potential importance of tumor-specific promoter systems, examples of where gene therapy has succeeded, the challenge of targeting all cancer cells, the advantages of targeting the tumor stroma and immunocytes, and the logistic barriers to preparation of materials required for clinical trials. The need for substantial antitumor activity and the importance of clinical responses in phase I–II trials are also highlighted. Overall, this volume provides substantial perspective regarding the translational potential of cancer gene therapy.
Robert C. Bast
Maurie Markman
Ernest Hawk
The idea of gene therapy was first proposed to correct errors associated with genetic disease by supplementing defective or missing genes. Advances in DNA technology and in understanding the basis of genetic diseases gave high hopes that gene therapy would be the next big breakthrough in medicine. However, the journey ahead was not without challenges and roadblocks. In 1999, a tragedy occurred when an 18-year-old gene therapy trial participant, Jessie Gelsinger, died 4 days after receiving adenoviral treatment for a genetic disorder from a massive immune response that led to multiple organ failure. This incident caused a major setback in the gene therapy field and the US Food and Drug Administration placed a hold on active gene therapy trials. Yet another event that followed brought more bad news to the field. In 2003, five patients who received CD34+ hematopoietic (bone marrow) stem cells transduced with a retrovirus carrying the interleukin-2 receptor γ chain gene to treat inherited X-linked severe combined immunodeficiency (SCID-XI) developed T-cell leukemia. One patient later died. Despite the dismissal of promising hopes of gene therapy in the early days as a result of these events, there is now optimism as more current research data have shown substantial progress in the clinical development of gene therapy after years of intense investigations to improve vector design and safety. Several successful gene therapy trials, including treatment of an inherited eye disease (Leber’s congential amaurosis), Parkinson’s disease, blood disorders, SCID-XI, adenosine deaminase-deficient SCID, and Siemerling–Creutzfeldt disease (X-linked adrenoleukodystrophy), have been reported in the last few years. Most recently, two studies published in July 2013 in Science reported clinical efficacy in lentivirial-mediated gene therapy to treat metachromatic leukodystrophy and Wiskott–Aldrich symdrome (see Chapter 2 for more details). In addition to human trials, studies conducted in canines showed that achromatopsia (an inherited form of total color blindness), diabetes, and Duchenne muscular dystrophy were successfully treated by gene therapy; these encouraging findings will undoubtedly continue to pave the way for conducting human clinical trials to develop new drugs to treat these diseases.
While no gene therapy has yet been approved in the USA, two have been approved for use in other parts of the world. The Chinese State Federal Drug Administration approved the world’s first gene therapy to treat head and neck cancer using Gencidine, an adenoviral vector expressing tumor suppressor p53. However, concerns about the therapeutic efficacy have been raised [1], and there are no further reported clinical outcomes after a decade of approval. In 2012, the European Commission approved the first gene therapy product (Glybera) in the Western world to treat lipoprotein lipase deficiency, a rare inherited disease of fat metabolism. The company uniQure is currently seeking regulatory approval in the USA, Canada, and other countries.
Cancer, cardiovascular, and infectious diseases, among many others, are also targets of gene therapy. Adenovirus remains the most popular type of vector used in gene therapy clinical trials worldwide, followed by retrovirus, naked/plasmid DNA, vaccinia virus, and lipofection in the top five. For viral vectors, the important parts of the virus required for gene delivery are kept and those that are not required are deleted, and the development of self-inactivating integrating viruses such as retrovirus and lentivirus eliminates the transactivation of neighboring genes after integration. Current investigations also continue to broaden the viral vectors’ cell host range. For non-viral vectors, improvements have focused on the delivery system for therapeutic agents, including plasmid DNA, RNA interference (RNAi), and microRNAs, by increasing cellular uptake, protecting against microphage digestion, and optimizing nucleic acid payload release.
In the USA, clinical studies must be reviewed by regulatory committees such as the Institutional Review Board (IRB), Food and Drug Administration (FDA), Institutional Biosafety Committee (IBC), and Recombinant DNA Advisory Committee (RAC). Moreover, manufacture must also comply with Good Manufacturing Practice (GMP) guidelines set out by the FDA. The development of sufficient manufacturing capacity to meet the clinical demands after gene therapy attains approval is another concern.
The discovery of monoclonal antibodies brought much excitement as a new treatment modality in early 1980s. However, the lack of efficacy and the rapid clearance of murine monoclonal antibodies due to the development of human antimouse antibodies in patients led to the failure of many clinical trials. Nonetheless, perseverance allowed the development of technological improvements resulting in the eventual clinical success of monoclonal antibodies, which are now a standard approach for producing therapeutics targeting cell surface receptors. In a similar way, further improvements in gene therapy may allow this approach to follow the successful journey of monoclonal antibodies.
To ensure that gene therapy can be successfully developed into new drugs following the fate of monoclonal antibodies, there are several areas needing critical improvement, including efficient delivery, specificity, and well-designed clinical trials. In this book, we have invited experts to discuss the current updates on cancer gene therapy. The opening chapter by Cerullo et al. describes various types of viral therapy, particularly DNA viruses (adenovirus, vaccinia virus, herpes virus, parvovirus) and provides examples of their use in clinical studies. The following chapter by Zhou et al. focuses on the principal types and evolution of lentiviruses in cancer and HIV therapy with special interest in gene silencing by RNAi. The next two chapters describe non-viral delivery systems. First, in Chapter 3 Najjar et al. review various methods of plasmid DNA delivery, optimization of gene expression, and their application for therapy including cancer. Satterlee and Huang then explain in Chapter 4 the design and challenges of nanoparticles to deliver therapeutic RNAi. In the second part, starting with Chapter 5, Hsu et al. provide an introduction to the clinical applications of tissue-specific and cancer-targeting promoters in cancer gene therapy. As aberrant microRNA expression has been implicated in promoting and initiating carcinogenesis, in Chapter 6 Ling and Calin present an overview of the role of microRNAs in cancer and other diseases and discuss examples of anti-microRNA therapeutics.
The last part of the book provides some insight on the regulatory compliance of gene therapy clinical trials focusing on manufacturing regulations of viral vectors by Gee and Mei in Chapter 7 and review processes and requirements prior to obtaining FDA approval by Grilley in Chapter 8. In the closing chapter, Brenner discusses the tasks that must be accomplished to make gene therapy drugs more broadly applicable and the improvements in clinical trial design, as the development pathway of cancer gene therapy is distinct from and more complex than the traditional pharmaceutical model. It is our hope that this book can facilitate the maturation of gene therapy for its clinical application.
Malcolm K. Brenner
Mien-Chie Hung