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Early-region (E1)-deleted, replication-defective adenovectors have been widely used in preclinical and clinical studies of cancer gene therapy. Recently, the use of conditional replicating or oncolytic adenovectors in cancer gene therapy or virotherapy has received much attention. Clinical trials with E1-deleted adenovectors and oncolytic adenovirus have shown that adenovector-mediated cancer gene therapy is well tolerated and can produce clinical responses in patients with advanced diseases. Moreover, numerous strategies to improve vector safety and therapeutic efficacy have been explored, including vector modification and the development of vector formulations to enhance transduction efficiency, to modulate tropism for vector targeting, to improve controlled or tissue-specific transgene expression, and to reduce vector-related toxicity. Yet, much has to be improved in this type of vector system to ensure its future success in clinical applications.

To date, over 60% of all gene therapy clinical trials in the United States have focused on the development and validation of new therapies for cancer. Many of these trials utilize Ad vectors as novel anticancer therapeutics. In recent years, however, initial enthusiasm and high expectations for successful clinical application of Ad-based vectors as efficient anticancer therapeutics has been dampened based on the data obtained during a series of clinical trials. Along with the major concerns over the safety of systemic Ad application, which was found to be associated with immediate innate and inflammatory host responses and can also lead to fatalities, such issues as rapid clearance of the bulk of administered vector by cells of the reticulo-endothelial system, neutralization of virus particles by highly prevalent pre-existing antibodies, and poor transduction of primary tumors resulting from low-level Ad receptor expression and/or anatomical barriers, including extracellular matrix surrounding tumors, have established a great need for research to further improve existing Ad vectors and unravel their true therapeutic potential as anticancer agents. This chapter reviews and discusses the current status, limitations and future challenges for the Ad vector development field with respect to their efficacy, toxicity and immunogenicity.

Retroviruses have been widely used as gene transfer vectors, and in fact represent the vector system used in the majority of clinical gene therapy trials for cancer to date. In an ex vivo setting, conventional replication-defective oncoretrovirus vectors can reliably and efficiently achieve permanent gene transfer which is selective for dividing cells; however, successful application of these vectors in vivo has been difficult because of their relatively low-transduction efficiency. Recently, however, the field has been revitalized by the advent of significant improvements in basic retrovirus vector technology, including the development of lentivirus-based vectors which are capable of efficient gene transfer even to quiescent nondividing cells, and tumor-selective replication-competent retrovirus vectors which progressively transduce cancer cells as the virus spreads through the tumor. This chapter reviews these important recent developments and their potential utility for gene therapy of cancer.

Vaccinia virus has been studied extensively since its discovery as a smallpox vaccine in 1798. Its use as a smallpox vaccine documented its safety profile. It was later found that its large size and ability to accept large fragments of DNA combined with its natural tumor affinity make it an attractive agent for cancer therapy. This chapter discusses the history of the vaccinia, the various strains available, the biology of the virus as well as the steps in creating recombinants. The various clinical and safety considerations will be addressed. We will also discuss the various methods used to treat cancer using the vaccinia virus and will review the recent clinical trials using vaccinia in the treatment of cancer.

Inspired by reports that viral infection might be capable of promoting tumor regression published in the early 20th century, investigators have struggled to identify a suitable virus, which though unable to cause disease, retained the capability to replicate in cancer cells. In principal, the productive growth of the virus would kill or lyse malignant cells and the newly minted viral progeny would spread the infection, resulting ultimately in the destruction of the tumor by a process termed viral oncolysis. Fueled by revolutionary advances in molecular biology that enabled a new understanding of viral virulence at the genetic level, nonpathogenic strains of human viruses have been engineered in the laboratory and their oncolytic ability evaluated in animal models of human cancer. This chapter chronicles the milestones in engineering oncolytic strains of herpes simplex virus type 1, highlighting different stages of development beginning with the pioneering use of recombinant viruses produced in the laboratory, accompanied by a discussion of key design innovations which upon incorporation into HSV-1 oncolytic strains, substantially improved both their safety and efficacy, and summarizes recent experiences in phase I clinical trials.

Alphavirus vectors can infect a broad range of mammalian cells both in cell cultures and in vivo. The presence of the RNA replicon generates extreme RNA levels in infected cells, which is the basis for the very high levels of heterologous gene expression. Application of replication-deficient vectors leads to short-term expression, which makes these vectors highly attractive for cancer gene therapy. Alphaviruses can be used as vaccine vectors for both prophylactic and therapeutic applications. In this context, the P185 tumor antigen and human papilloma virus gene E7, when administered in mice, resulted in protection against tumor challenge and tumor regression in animals with pre-existing tumors. Alphavirus vectors carrying therapeutic or toxic genes used for intratumoral injections have demonstrated efficient tumor regression. For systemic delivery, expression targeting has been obtained by the introduction of targeting sequences in the envelope structure of the virus. Alternatively, alphavirus particles have been encapsulated in liposome, which can target tumor cells.

The ability of RNA viruses to efficiently reproduce in transformed cells was first recognized nearly 100 yr ago. However, it wasn’t until the late 1990s that a resurrection of the interest in the ability of certain viruses to preferentially replicate in malignant cells and less so in normal cells occurred, the curiosity being to evaluate whether these agents could be useful in cancer therapy regimes. It was following these reports, demonstrating that DNA viruses such as adenovirus and herpes simplex virus (HSV) could act as antineoplastic agents, that similar encouraging investigations were conducted using RNA viruses such as reovirus and Newcastle Disease virus, vesicular stomatitis Virus (VSV), and measles virus (MV). Here we will review the use of RNA viruses as oncolytic agents in the treatment of malignant disease, focusing on the negative-stranded RNA virus, VSV. The general mechanisms by which oncolytic viruses such as VSV achieve their antitumor effectiveness and specificity are discussed, including the role of the innate immune system involving the interferon response.

Parvoviruses are among the smallest of eukaryotic viruses. The association of parvovirus with cancer has been reported much before realizing the potential application of parvovirus-based vectors in cancer gene therapy. Unique characteristics of paroviruses such as nonpathogenicity, antioncogenicity, and methods of efficient recombinant vector production have drawn more attention toward utilizing parvovirus-based vectors in cancer gene therapy. Although more than 30 different parvoviruses have been identified thus far, recombinant vectors derived from adeno-associated virus (AAV), minute virus of mice (MVM), LuIII and parvovirus H1 have been successfully tested in many preclinical models of human diseases including cancer. This chapter focuses on the potential of nonreplicating and autonomously replicating parvoviral vectors in cancer gene therapy including strategies that target tumor cells directly or indirectly.

Gene therapy requires efficient vectors for delivering therapeutic genes. Advances in developments of nonviral vectors have been established for improving the efficiency of gene delivery. This chapter describes different nonviral methods as well as their applications. Some new directions in developing nonviral vectors are also discussed.

Oncogenes, tumor suppressor genes, and apoptosis-inducing genes play critical roles in cell proliferation, differentiation, and death. Their expressions are frequently altered in cancer cells by gene mutation, deletion, rearrangement, inactivation, or overexpression. Some of these alterations are directly related to the development and maintenance of malignant phenotypes; others relate to the response of cancer cells to various anticancer therapies. Both preclinical and clinical studies have indicated that restoring the normal function of these genes may be an effective means of cancer therapy although full realization of any anticancer benefit will depend on effective delivery of these genes to cancer cells.