Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 287

in cells expressing endogeneous wild-type p53 , demonstrated that injection of adeno-
virus expressing p53 into rats with brain tumors caused a decrease in tumor size [134] .
The encouraging results of these preclinical studies of p53 using adenoviral vector
led to a clinical trial. The clinical trial of p53 delivery using adenovirus resulted in
improvement in median survival time of patients [135] . Another commonly affected
cell-cycle pathway in gliomas is the retinoblastoma protein/cyclin-dependent kinases/
cyclin-dependent kinase inhibitors (CDKN) circuit. Preliminary studies restoring the
genomic region of CDKN2A/CDKN2B in glioblastoma cell lines have also demon-
strated significant tumor growth arrest by apoptosis [136] .
6.3.4.3 Genetic Immune Modulation
Since brain tumors have low immunogenicity and tend to bypass immune responses,
several strategies have been aimed to modulate the host's immune responses. The
studies utilizing delivery of MHC class I molecules and B7 costimulatory molecules
resulted in tumor regression [137,138] . Moreover, the delivery of B7 coupled with
systemic IL-12 administration resulted in intracranial tumor growth inhibition [139] .
Several studies have been performed by infecting tumor cells ex vivo with cytokine
genes (IL-2, IL-4, IL-12, and INF-) and then reimplanting the cells to sustain para-
crine secretion of cytokines within the tumor [140-143] . Another way to induce tumor
immunogenicity is by directly stimulating T-cells to proliferate by inducing the produc-
tion of IL-2/IL-4 within the tumor [144] . In a clinical trial, an adenovirus vector was
used for the delivery of human IFN- in patients with recurrent glioma. The results
showed a dose-related inflammation and necrosis suggestive of a biological effect from
the transferred gene. The treatment was well tolerated in all the patients [145] .
6.3.4.4 Antiangiogenic and Antisense Gene Therapy
Because the expansion of tumors is dependent upon angiogenesis, antiangiogenesis
was proposed as a therapeutic strategy, especially for highly vascular tumors like glio-
blastomas. The use of antivascular endothelial growth factor (anti-VEGF) antibodies
resulted in the suppression of tumor growth by inhibiting angiogenesis [146] . Antisense
cDNA/oligonucleotides like VEGF cDNA also showed promising results in controlling
gliomas, with significant tumor regression [147] . A study has shown that the delivery
of antisense oligodeoxy-nucleotides in human glioma cells results in tumor suppression
through specific inhibition of c-sis protein synthesis and cell proliferation [148] .
6.3.4.5 Oncolytic Viruses
Herpes simplex virus has been genetically engineered to lack genes to encode
enzymes necessary for viral DNA synthesis and/or replication. Infection of these
HSV-1 mutants to actively dividing tumor cells resulted in the proliferation of multi-
ple progeny virions or the production of new antigens on the tumor cell surface, with
subsequent immunological rejection and cell death [149] . In clinical trials, use of
HSV-1 (G207) for brain tumors resulted in decreased tumor growth with prolonged
survival [150,151] .