Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 286

many SCLC and NSCLC cell lines. The utility of these antigens is yet to be determined
in lung cancer immunotherapy [118,119] . Another approach for cancer immunotherapy
involved the use of whole cancer cells as a source of tumor antigen to express immuno-
modulatory molecules, such as cytokines or costimulatory molecules like GM-CSF to
enhance their immunogenicity [120] .
6.3.3.5 Oncolytic Viruses
ONYX-015 is a replication-specific adenovirus with a deletion in the E1B -55 kD gene
region required for inhibition of wild-type p53 function. Therefore, viral replication is
prevented in cells with normal p53 function but permitted in tumor cells with mutant
p53 , where it leads to cell death [70] . A recent clinical study confirmed both the safety
and feasibility of intravenously administered ONYX-015 in patients with end-stage
metastatic lung cancers [121] .
6.3.4 Brain Cancer
In the United States, an estimated 22,070 new cases of brain and other nervous sys-
tem cancers (12,010 in men and 10,060 in women) have been diagnosed in 2009, and
12,920 deaths (7330 in men, 5590 in women) have been estimated to occur due to
this disease [39] . Apart from the normal problems in gene therapy, gene delivery to
the brain has to overcome obstacles such as the blood-brain barrier and limited space
within the brain, which restrict the volume of gene transfer vectors that can be injected
when administered locally [122] .
6.3.4.1 Suicide Gene Therapy
The HSV- tk gene delivered using adenovirus and retrovirus in animal models of brain
tumors has resulted in tumor regression [123,124] . Once expressed in brain tumor
cells, HSV- tk converts the nontoxic nucleoside analogs, such as GCV, acyclovir, or
valacyclovir (VCV), into a cytotoxic molecule. Furthermore, preclinical experiments
in animal species demonstrated marked tumor elimination despite gene transfer into
only a small fraction of tumor cells. This cytotoxic effect of transduced cells on adja-
cent nontransduced cells is termed the “bystander effect” [125] .
A number of clinical trials for brain tumors utilized HSV- tk delivery using a ret-
rovirus, followed by the administration of GCV either orally or systematically. The
results of all these clinical trials showed a reduction in the tumor volume and improve-
ment in the average survival time period of patients [126-129] . Cytosine deaminase/
5-fluorocytosine and cytochrome P450 2B1/cyclophosphamide systems have also
been used for experimental human glioblastomas [130,131] .
6.3.4.2 Transfer of Tumor Suppressor Genes and Cell-Cycle Modulators
Like other tumors, the majority of brain gliomas have functional inactivation of p53
[132] . Restoration of normal (wild-type) p53 functions in p53 mutant glioblastoma
cells, using adenoviral vectors, was shown to be successful in inducing apoptosis
[133] . Furthermore, overexpression of wild-type p53 suppressed tumor growth, even