Page 272 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Molecular/Targeted Therapy of Cancer

SECTION A: GENE THERAPY FOR CANCER past 20 years, and a herculean effort has been placed into devel-
oping robust vector systems for clinical use. The major delivery
vehicles that have been exploited fall into the two broad catego-
DAVID J. ARGYLE ries of viral vectors and nonviral (usually plasmid-based) vectors.
Vector systems are summarized in Table 15.1 and Fig. 15.1.
Since its development, recombinant DNA technology has been The great advantage to viral vectors for gene delivery is their abil-
vigorously applied to the advancement of medicine. New molecu- ity to infect cells and our ability to exploit their replicative machin-
lar techniques have been used to study the role of specific genes ery. The majority of systems use replication-defective viruses to
and their products in disease, to improve diagnosis, and to produce overcome concerns that recombination within the host may lead to
novel therapeutics. Gene therapy, in its simplest definition, is the the production of wild-type virus with pathogenic potential. The
introduction of genes into cells in vivo to treat a disease, and it has common systems rely on oncogenic retroviruses (e.g., murine leu-
1
been applied to many chronic, intractable diseases such as single kemia virus [MuLV]), adenoviruses (e.g., human adenovirus type 5
gene defects and cancer. This definition could probably now be [AD5]), adeno-associated viruses (AAVs), or lentiviruses. Lentiviral
extended to the delivery of all forms of nucleic acids for treatment. vectors have a better safety profile than retroviral vectors and are
More than 2000 clinical gene therapy trials have been conducted more efficient at delivering genes to nondividing cells. 6–11 Among
worldwide, and as could be predicted with any developing tech- the various viral-based vector systems, the AAVs are proving to have
nology, there have been a litany of disappointments interspersed the greatest utility in the treatment of human diseases. Alipogene
with a few prominent successes, particularly in ocular and immu- tiparvovec (marketed as Glybera), an AAV-vector based treatment
nodeficiency diseases. Cancer has proved to be an attractive target for lipoprotein lipase deficiency, was one of the first gene therapy
2
for gene therapy, with clinical studies that have included delivery products to be licensed by the European Medicines Agency in 2012
2
of “killing genes,” immune-modulating genes, and genes that can and was an important milestone in drug development ; however,
1
alter host tumor microenvironment (e.g., tumor vasculature). the drug was withdrawn in 2017 by the parent company because of
Early human cancer trials, including those to deactivate oncogenes lack of demand and the 1 million euro price tag.
or restore tumor suppressor gene function, proved to have little Most of the viral systems for cancer gene therapy involve
clinical utility, but the past 20 years have seen a growing number the local delivery of virus to tumor deposits (e.g., by intratu-
of clinical successes in human medicine that have paralleled our moral injection), or ex vivo delivery of transgene to autologous
increased understanding of and experience with the delivery tech- cells. Systemic delivery of virus is hindered by rapid clearance of
nology. 2–5 Furthermore, the exponential growth of data around viruses from the body by the immune and complement systems.
cancer genomes, biology, and immunology is allowing the exploi- To overcome this, work has progressed to explore cellular deliv-
tation of gene therapy technologies to improve patient outcomes ery of viruses by the systemic route. In this delivery system, viral
and a drive toward precision medicine. The gene therapy field in producer cells are delivered to the patient, and virus production
veterinary oncology has proved to be much slower that in human is triggered when the cells reach the tumor. Endothelial cells, T
medicine, hindered by the paucity of biology data, costs of develop- cells, macrophages, dendritic cells, and mesenchymal stem cells
ment, and (in some cases), the regulatory environment. However, a (MSCs) are also being explored as potential cell delivery systems.
number of studies are now emerging that suggest that this technol- The advantage of these systems is that virus could potentially be
ogy may prove to be a useful adjunct in veterinary oncology. delivered to metastatic disease and primary tumors. 12–16
Concerns relating to virus safety, an inability to produce high
Delivery Vehicles for Cancer Gene Therapy enough viral titers for clinical trials, and the cost of viral vec-
tors have led to the development of nonviral delivery systems for
Effective gene therapy relies on our ability to introduce genes effi- gene therapy. 17–18 Such methodologies have included the use of
ciently into target cells or tissues in vivo, or the ex vivo delivery of cationic liposomes, “naked” (plasmid) DNA, synthetic viruses,
genes to autologous cells and subsequent adoptive transfer back transposons, and bacteria (summarized in Table 15.1). Cationic
to the patient. It is the efficient and safe transfer of genes that has liposomes are microscopic vesicles that enter cells by endocyto-
proved to be the greatest hurdle to clinical development over the sis and have been used to safely and efficiently deliver genes to

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