Title Details

Dr K. J. Harrington, Targeted Therapy Laboratory, Cancer Research UK, Centre for Cell and Molecular Biology, Institute of Cancer Research, London, UK.

Dr H. S. Pandha, Department of Medical Oncology, St. George's Hospital Medical School, London, UK.

Professor R. G. Vile, Molecular Medicine Program,?Mayo Clinic, Rochester, USA.

Foreword xiii

Preface xv

Contributors xvii

1 Adenoviruses 1
Kate Relph, Kevin J. Harrington, Alan Melcher and Hardev S. Pandha

1.1 Introduction 1

1.2 Viral structure and life cycle 1

1.3 Adenoviral vectors 5

1.4 Targeting adenoviral vectors 6

1.5 Clinical applications of adenoviral gene therapy 7

1.6 Adenoviral vectors for immunotherapy 7

1.7 Adenoviral vectors for suicide gene therapy 10

1.8 Adenoviral vectors for gene replacement therapy 11

1.9 Oncolytic adenoviral therapy 12

1.10 Adverse outcomes of adenoviral gene therapy 13

1.11 Summary 13

References 14

2 Application of HSV-1 vectors to the treatment of cancer 19
Paola Grandi, Kiflai Bein, Costas G. Hadjipanayis, Darren Wolfe, Xandra O. Breakefield and Joseph C. Glorioso

2.1 Introduction 19

2.2 Basic biology of HSV 19

2.3 Replication competent or oncolytic vectors 24

2.4 Replication defective vectors 28

2.5 Amplicons 30

2.6 Impediments to the efficacy of HSV vectors for cancer gene therapy 32

2.7 Strategies to enhance the efficacy and specificity of HSV vectors for cancer gene therapy 36

2.8 Summary and conclusions 42

Acknowledgements 42

References 42

3 Adeno-associated virus 55
Selvarangan Ponnazhagan

3.1 Introduction 55

3.2 Biology and life cycle of AAV 55

3.3 AAV serotypes 57

3.4 Production of recombinant AAV 57

3.5 Gene therapy for cancer treatment 57

3.6 Anti-oncogenic properties of AAV 58

3.7 Molecular chemotherapy studies with rAAV 59

3.8 AAV-mediated sustained transgene expression as a potential cancer gene therapy strategy 59

3.9 rAAV vectors have advantages in stimulating T helper 1/cytotoxic T lymphocyte responses 60

3.10 rAAV vectors can be used to initiate immune responses 61

3.11 Altering AAV tropism for tumour-specific delivery 62

3.12 Clinical trials involving rAAV 62

3.13 Conclusion 63

Acknowledgements 63

References 63

4 Retroviruses 69
Simon Chowdhury and Yasuhiro Ikeda

4.1 Introduction 69

4.2 Structure of retroviral particles 69

4.3 Retroviral genome 69

4.4 Retroviral life cycle 70

4.5 Retroviral vectors 71

4.6 Safety of retroviral vectors: insertional mutagenesis 72

4.7 Gene therapy of X-linked SCID 72

4.8 Retroviral cancer gene therapy 75

4.9 Immunomodulatory approaches 78

4.10 Conclusions 79

References 80

5 Lentiviral vectors for cancer gene therapy 83
Antonia Follenzi and Elisa Vigna

5.1 Development of lentiviral vectors (LV) 83

5.2 Targeting of transgene expression 85

5.3 Host immune responses to LV and their transgene 86

5.4 Transgenesis 87

5.5 Haematopoietic stem cell gene transfer 87

5.6 Cancer treatment by LV 89

5.7 Approved clinical trials using LV 91

5.8 Conclusions 91

References 91

6 Poxviruses as immunomodulatory cancer therapeutics 95
Kevin J. Harrington, Hardev S. Pandha and Richard G. Vile

6.1 Introduction 95

6.2 General features of poxvirus structure and biology 95

6.3 Clinically applicable poxviruses 97

6.4 Poxviruses as potential cancer therapeutics 99

6.5 Clinical experience with poxviruses 102

6.6 Conclusions 110

References 110

7 Oncolytic herpes simplex viruses 115
Guy R. Simpson and Robert S. Coffin

7.1 Introduction 115

7.2 Herpes simplex virology 115

7.3 Properties of HSV relevant to oncolytic virus therapy 117

7.4 Mutations giving tumour-selective replication 118

7.5 Oncolytic HSV expressing fusogenic membrane glycoproteins (FMG) 125

7.6 Prodrug activation therapy and oncolytic HSV 126

7.7 Combination of oncolytic HSV with immunomodulatory gene expression 127

7.8 Combination of conventional therapies with oncolytic HSV 128

7.9 Summary 129

Acknowledgement 130

References 130

8 Selective tumour cell cytotoxicity by reoviridae – preclinical evidence and clinical trial results 139
Laura Vidal, Matt Coffey and Johann de Bono

8.1 Introduction 139

8.2 Reovirus structure 139

8.3 Reovirus replication 140

8.4 Reovirus and human infection 141

8.5 Oncolytic activitiy 142

8.6 Mechanism of reovirus-induced cytotoxicity 145

8.7 Preclinical experience 145

8.8 Immunogenicity 146

8.9 Clinical experience 146

8.10 Conclusions 147

References 148

9 Oncolytic vaccinia 151
M. Firdos Ziauddin and David L. Bartlett

9.1 Introduction 151

9.2 Biology of vaccinia virus 151

9.3 Tumour selectivity and antitumour effect 153

9.4 Improving antitumour effects through bystander effects 160

9.5 Immune response to vaccinia and vaccinia immune evasion strategies 161

9.6 Virus-driven antitumour immune response 163

9.7 Imaging 164

9.8 Current and potential clinical applications 165

References 166

10 Newcastle Disease virus: a promising vector for viral therapy of cancer 171
Volker Schirrmacher and Philippe Fournier

10.1 Introduction 171

10.2 Structure, taxonomy, pathogenicity and oncolytic properties of NDV 171

10.3 Human application and safety 172

10.4 Tumour-selective replication of NDV 174

10.5 Virally based cancer immunotherapy and danger signals 174

10.6 NDV: a danger signal inducing vector 175

10.7 The human cancer vaccine ATV-NDV 176

10.8 Pre-existing antitumour memory T cells from cancer patients and their activation by antitumour vaccination with ATV-NDV 177

10.9 Clinical trials of antitumour vaccination with ATV-NDV 177

10.10 NDV-specific recombinant bispecific antibodies to augment antitumour immune responses 179

10.11 NDV-binding bispecific fusion proteins to improve cancer specific virus targeting 180

10.12 Recombinant NDV as a new vector for vaccination and gene therapy 180

10.13 Conclusion 181

References 182

11 Vesicular stomatitis virus 187
John Bell, Kelly Parato and Harold Atkins

11.1 Introduction 187

11.2 VSV: genomic organization and life cycle 187

11.3 Host range and pathogenesis of VSV infection 188

11.4 Control of VSV infection by the innate type I interferon response 189

11.5 Cancer cells are insensitive to type I interferon 190

11.6 VSV preferentially replicates in and lyses tumour cells in vitro 190

11.7 VSV attenuation: enhanced tumour selectivity and therapeutic index 192

11.8 Engineered/recombinant VSV 192

11.9 VSV effectively eradicates tumours in vivo 193

11.10 VSV and the host immune response 194

11.11 Host immunity vs. therapeutic efficacy 195

11.12 VSV is a potent vaccine 195

11.13 Innate sensing of VSV and the antitumour response 196

11.14 So what is a good oncolytic virus? 197

11.15 Future challenges for VSV 198

References 199

12 Measles as an oncolytic virus 205
Adele Fielding

12.1 Introduction 205

12.2 Measles virus and the consequences of natural infection 205

12.3 MV vaccine 206

12.4 MV genetics and engineering 206

12.5 MV receptors 207

12.6 Animal models for the study of MV pathogenesis and oncolysis 207

12.7 Oncolytic activity of MV 208

12.8 Mechanism of specificity 208

12.9 Targeting MV entry 209

12.10 Enhancing the oncolytic activity of MV 210

12.11 Interactions with the immune system 210

12.12 Potential specific toxicities of clinical use of replicating attenuated MV 211

12.13 Clinical trials 211

12.14 Conclusions 212

References 212

13 Alphaviruses 217
Ryuya Yamanaka

13.1 Introduction 217

13.2 RNA viruses as gene expression vectors 218

13.3 The biology of alphaviruses 218

13.4 Heterologous gene expression using alphavirus vectors 220

13.5 Cancer gene therapy strategies using alphavirus vectors 221

13.6 Alphavirus vector development for gene therapy application 223

13.7 Conclusions 224

References 225

14 Tumour-suppressor gene therapy 229
Bingliang Fang and Jack A. Roth

14.1 Tumour-suppressor genes 229

14.2 Use of tumour-suppressing genes for cancer therapy 231

14.3 Clinical trials of p53 gene replacement 232

14.4 Tumour-suppressor gene therapy in multimodality anticancer treatment 233

14.5 Future prospects 235

Acknowledgements 235

References 236

15 RNA interference and dominant negative approaches 241
Charlotte Moss and Nick Lemoine

15.1 Introduction 241

15.2 Oligonucleotide agents 241

15.3 Mechanism of RNAi 242

15.4 RNAi and antisense compared 243

15.5 siRNA design 244

15.6 Off-target effects 244

15.7 Induction of innate immunity 246

15.8 Methods of delivery 247

15.9 Antisense 251

15.10 Dominant negative approaches 252

15.11 Research applications of siRNA 252

15.12 Therapeutic applications of siRNA 252

References 253

16 Gene-directed enzyme prodrug therapy 255
Silke Schepelmann, Douglas Hedley, Lesley M. Ogilvie and Caroline J. Springer

16.1 Introduction 255

16.2 Enzyme-prodrug systems for GDEPT 255

16.3 Gene delivery vectors for GDEPT 262

16.4 Conclusions 268

References 269

17 Immunomodulatory gene therapy 277
Denise Boulanger and Andrew Bateman

17.1 Introduction 277

17.2 Immunotherapy strategies using viral vectors 277

17.3 Viruses used as viral vectors in cancer immunotherapy 280

17.4 Clinical trials against specific TAA 283

17.5 Conclusions and future prospects 289

References 290

18 Antiangiogenic gene delivery 295
Anita T. Tandle and Steven K. Libutti

18.1 Angiogenesis: role in tumour development and metastasis 295

18.2 Targeting tumour vasculature as an approach for cancer treatment 297

18.3 Viral vectors to deliver antiangiogenic gene products 299

18.4 Viral targeting 303

18.5 Concluding remarks 306

References 306

19 Radiosensitization in viral gene therapy 313
Jula Veerapong, Kai A. Bickenbach and Ralph R. Weichselbaum

19.1 Introduction 313

19.2 Adenovirus 313

19.3 Adeno-associated viruses 314

19.4 Herpes simplex viruses 314

19.5 Enhancing the effect of radiation by delivering tumour suppressor genes 316

19.6 Virus-directed enzyme prodrug therapy 316

19.7 Conclusions 322

References 324

20 Radioisotope delivery 327
Inge D.L. Peerlinck and Georges Vassaux

20.1 Introduction 327

20.2 History of iodine therapy 327

20.3 Genetic therapy 330

20.4 Conclusion 338

References 338

21 Radioprotective gene therapy: current status and future goals 341
Joel S. Greenberger and Michael W. Epperly

21.1 Introduction 341

21.2 Organ-specific radiation protection: oral cavity/oropharynx 342

21.3 MnSOD-PL treatment reduces pulmonary irradiation damage 354

21.4 MnSOD-PL gene therapy down-modulates marrow cell migration to the lungs 357

21.5 MnSOD-PL systemic administration for radiation protection from TBI 358

21.6 Summary and future directions 359

References 360

22 Chemoprotective gene delivery 377
Michael Milsom, Axel Schambach, David Williams and Christopher Baum

22.1 Introduction 377

22.2 The promise of chemoselection strategies 377

22.3 The limitations of chemoselection strategies 381

22.4 Which expression level of chemoprotective genes is appropriate? 384

22.5 Vector design to achieve optimal expression levels 385

22.6 Exploring side effects of continued transgene expression and insufficient chemoprotection 387

22.7 The future: inducible expression of drug resistance genes 388

Acknowledgements 389

References 389

Index 393