Cancer Gene Therapy
Many human diseases are caused by inherited or acquired abnormalities in
gene expression or regulation. Gene therapy was developed as a means of
restoring lost or blocking abnormal gene functions.
Unlike conventional therapies, gene therapy for cancer promises
specific targeting of cancer cells with fewer toxic effects.
The hope is to cure cancer.
Despite the presence of cancer associated antigens,
cancer cells are poor immunogens.
Anti-cancer immune response can be enhanced by
increasing cancer cell immunogenicity or boosting effector (immune)
Not until recently, this aim can be reached by
introducing genes into cancer or effector cells, an approach
known as transgenic immunotherapy. This approach includes
cancer vaccines, cancer infiltrating lymphocyte adoptive immunotherapy,
lymphocyte cancer homing, and
antibody-dependent cell-mediated cytotoxicity (ADCC).
Recombinant cancer vaccines are
generated by transfecting genes into cancer cells.
Such vaccines elicit an immune response to the primary cancer as well as
a systemic anti-cancer response with immune memory.
The technique involves
primary culture of the cancer cells, ex vivo transduction of the cells
with the selected gene, UV irradiation the genetically modified cells, and
reinjection of these cells back into the patient.
There are three different types of genes used for this purpose.
Genes encoding proteins foreign to the host, such as viral
oncogenes and carcinoembryonic antigens (CEA).
Genes encoding accessory proteins for costimulation of T cell
activation, such as B7.
During the antigen recognition process,
the T cell costimulatory ligand interaction between B7 and CD28
produces a second signal required for CD8+ CTL-dependent antigen priming
and primary T lymphocyte activation.
Genes encoding cytokines, which are
the key modulators of host immune and inflammatory responses.
Among several cytokines explored, interleukin-2 (IL-2)
has received the most attention.
IL-2, secreted by activated CD4+ (helper) T cells,
activates CD8+ CTL (cytolytic) and NK (natural killer) cells responsible
for perishing cancer cells.
Another possible cytokine candidate is TNF-alpha (tumor necrosis factor),
which has limited use in cancer therapy due to toxicity.
Loss of cancer-suppressor genes has been recognized as a cause of
cancer. p53 is probably the best-known tumor suppressor gene.
Approximately 50% to 60% of human cancers are associated
with a mutated p53 gene or lack of p53 expression.
p53-deficient cancers are often resistant to therapy.
Restoration of wild-type p53 expression
led to inhibition of cell growth,
selectively inducing apoptosis of cancer
cells, sensitization of cancer cells to chemotherapy and radiation
therapy, decreased metastasis, and prolonged survival.
A proto-oncogene is
the normal, cellular equivalent of an oncogene that is
usually a gene involved in the signaling or regulation of cell growth.
A single mutant allele or oncogene is sufficient
for malignant transformation.
Abnormal functions of oncogenes can be turned off
by correcting the mutant genetic sequence itself or
interfering with its expression.
While it is difficult to correct the mutant sequence direct,
blocking genetic expression might be accomplished through
antisense sequences or ribozymes targeted specifically to the
oncogenic messenger RNA. Antisense oligodeoxynucleotides against
c-myb, c-muc, H-c-ras, bcr/abl, PCNA, CDC2, and EGF-related growth factor
have been shown to inhibit cancer cell growth.
Walther, W. (Editor), Stein, U. (Editor). (2000)
Gene Therapy of Cancer : Methods and Protocols
(Methods in Molecular Medicine, 35). Humana Press.