Chapter 21 - Gene therapy
Section snippets
The HSV-TK/ganciclovir clinical studies
The first attempts to use nonreplicating retroviruses as vectors to deliver the HSV-TK gene to actual patients with glioma were undertaken during the 1990s. These early studies demonstrated the safety and feasibility of a single intratumoral injection of retrovirus-producing cells (RVPCs) followed by the intravascular (intravenous or intra-arterial) delivery of ganciclovir (GCV) (Ram et al., 1997, Shand et al., 1999). Since then, several clinical trials have evaluated the safety and efficacy of
The Ad-p53 clinical trial
Greater insights into brain tumor biology indicated that the transfer of p53 held promise as an alternative therapy for human gliomas. Consequently, a group of investigators at M.D. Anderson Cancer Center in Houston undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). A two-stage approach was used in this study in order to obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral
The herpes simplex virus
Viruses that can kill the host cell during replication have attracted much interest as a means of specifically killing tumor cells, and such oncolytic virotherapy has indeed now made its way into clinical trials. If such viral replication can be limited predominantly to tumor cells, in situ viral multiplication and the spread of viral infection throughout the tumor mass can be controlled and targeted. The important consequence of accomplishing both these aims is that gene therapy will not only
Reoviruses
A reovirus is a naturally occurring oncolytic virus that usurps for its replication the activated Ras-signaling pathways of tumor cells that in most malignant gliomas are activated via upstream signaling by receptor tyrosine kinases (see Figure 21.1). In preclinical studies, reovirus killed 83% of 24 established malignant glioma cell lines tested. In addition, it caused a dramatic and often complete tumor regression in vivo in two subcutaneous glioma mouse models and in an intracerebral human
Oncolytic adenoviruses targeting the p53 pathway
These viruses are not delivering p53 but rather are using p53 defects in cancer cells to replicate and propagate killing glioma cells by lysis. The adenoviral protein E1B55kD is thought to block p53 activity, thereby preventing apoptosis and allowing adenoviral replication. This mechanism has been exploited as a means of achieving tumor selectivity (see Figure 21.1). In one such effort, some laboratories initially showed that a mutant strain of adenovirus that lacks E1B55kD could selectively
Oncolytic adenoviruses targeting the Rb pathway
After the ntroduction of E1B mutant adenoviruses into clinical use, researchers began to assess E1A mutants (see Figure 21.1), which they found to be more potent than the E1B mutants. In the first construct in this class, the Rb protein-binding site was deleted in the E1A gene, a design prompted by three observations: (1) the finding that the Rb protein is a primary factor in maintaining fully differentiated cells that have been arrested in a postmitotic state; (2) the discovery that Rb protein
Oncolytic viruses and chemotherapy
There is now evidence suggesting that the antitumoral effect of oncolytic adenoviruses is enhanced when they are administered in combination with chemotherapy, and vice versa (Khuri et al., 2000). In one such approach, oncolytic viruses are being studied in combination with topoisomerase I-dependent chemotherapy (i.e., S phase-specific agents). Given that adenovirus infection increases topoisomerase I and II levels (Romig and Richter, 1990), and that topoisomerase I expression was found to
Oncolytic herpes viruses and DNA repair
Mammalian cells possess complex machinery to detect and repair damaged DNA that is also useful for recognizing viral genetic material. Some viruses, such as adenoviruses, need to inactivate this machinery in order to replicate; others, such as herpes viruses, utilize the DNA repair mechanism to their own benefit (Weitzman et al., 2004). However, given that several anticancer agents cause DNA damage as a route to destroy cancer cells, researchers are attempting to understand both processes and
Conclusion
Improving our understanding of the mechanisms of viral oncolysis and the immune responses that viruses induce, as well as improving our ability to image these viruses in vivo, should make this therapeutic approach safer and more effective. Multimodal therapy will figure prominently in the future for the treatment of genetically and phenotypically heterogeneous neoplasias, including gliomas, with the inclusion of oncolytic adenoviruses essential for improving the therapeutic effect of the
Acknowledgments
We thank Betty Notzon (Department of Scientific Publications, The University of Texas M.D. Anderson Cancer Center, Houston, TX) and Jan Esenwein (Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX) for editorial assistance. We greatly appreciate the support of the Marcus Foundation.
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2012, Biochemical and Biophysical Research CommunicationsCitation Excerpt :These include successful treatments of patients with retinal disease [7], Leber’s Congenital Amaurosis [8], X-linked SCID [9], ADA-SCID [10], adrenoleukodystrophy [11], heart failure [12], AD [13] and PD [14]. These recent clinical successes have aroused a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field [15,16]. However, successful gene therapy largely depends on delivery systems which are safe, easy to apply and provide efficient transgenic expression in vivo.
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