Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 283

6.3.2.2.4 Delivery of the Melanoma Differentiation-Associated
Protein 7 Gene
MDA-7 is a novel tumor suppressor gene, and its transfer into tumor cells causes
growth suppression and apoptosis [88] . The adenoviral MDA-7 system is under inves-
tigation for cancer gene therapy [89] .
6.3.2.3 Immunomodulation Gene Therapy
Advances in gene transfer technology have greatly expanded the opportunities for
developing immunotherapy strategies for breast carcinoma. Genetic immunotherapy
approaches include the transfer of genes encoding cytokines and costimulatory mol-
ecules to modulate immune function, as well as genetic immunization strategies that
rely on the delivery of cloned tumor antigens.
6.3.2.3.1 Transfer of Cytokine Genes
The intratumoral injections of adenovirus-expressing human IL-2 and IL-12 have
resulted into tumor regression in mice models [90] . In a clinical trial focusing on met-
astatic breast cancer and melanoma, different doses of Ad/IL-2 were injected subcuta-
neously in 23 patients. Local inflammation occurs in patients, especially at high doses.
IL-2 can be detected 48 h after injection, and reduction in the diameter of tumors was
observed [91] . In another phase I trial, the primary dermal fibroblasts from patients
were transduced with retroviral vectors carrying the human IL-12 gene ex vivo . These
IL-12-transduced autologous fibroblasts were injected peritumorally into nine patients
with disseminated cancer, including five breast cancer patients. The results showed
tumor regression in four patients, with no toxicities [92] . The other strategy to aug-
ment the immune system for cancer gene therapy is the transfer of tumor necrosis fac-
tor (TNF). Retroviral transfer of the TNF and Neo genes into tumor cells ex vivo and
subcutaneous injection of tumor cells resulted in activating immune response to tumor
cells in patients [93] .
6.3.2.3.2 Transfer of the Costimulatory Molecule Gene
The efficient activation of T-cells requires costimulatory signals in addition to an anti-
gen-specific signal received by the T-cell receptor/CD3 complex. These nonspecific,
costimulatory signals are provided by the CD28 receptor on T-cells and their ligands
belonging to the B7 family—B7-1 (CD80) and B7-2 (CD86). The antitumoral effects
of IL-2 and IL-12 have been well established in breast cancer in preclinical and clini-
cal settings [90,91,94] .
6.3.3 Lung Cancer
Lung cancer is the leading cause of cancer death in both men and women worldwide.
An estimated 219,440 new cases in the USA (116,090 in men and 103,350 in women)
of lung and bronchus cancer have been diagnosed in 2009 and 159,390 deaths (88,900
in men, 70,490 in women) have occurred due to lung cancer [39] . The failure of
conventional chemotherapy along with surgery and radiation occurs because of the
tumors' multiresistance to chemotherapy and radiation. Combinations of currently