WASHINGTONGene therapy is unlikely to cure cancer on its
own, but may enhance existing treatments when used in combination, said
Chuan-Yuan Li, PhD, of Duke University Medical Center. "Combining gene
therapy with radiation therapy produces a synergistic effect on tumors and
merits further study," he said at the Susan G. Komen Breast Cancer
Foundation grants conference "Reaching for the Cure."
Dr. Li said that there are two problems to be overcome with
gene therapy: How to deliver the genes to target tissues or organs and how to
control where and when the gene therapy is expressed. An added requirement in
cancer is that any therapy needs to eliminate 100% of the tumor or it will
In his work, Dr. Li used adenovirus genetically engineered to
deliver the therapeutic genes. Adenoviruses are useful because many of their
own genes can be removed and replaced with therapeutic genes without affecting
their ability to infect.
Dr. Li inserted genes expressing the cytokine interleukin-12
(IL-12) and the immunostimulatory molecule B7.1 (AdIL12/B7.1). He injected
nonimmu-nogenic mouse mammary tumor cells (4T1) subcutaneously into the legs of
the mice, irradiated the tumors, and then injected the viral vectors. The
combined gene and radiation therapies produced effects on the tumors greater
than either therapy alone.
However, Dr. Li also found that the tumorally injected virus
may disseminate beyond the tumor to the liver, lung, and spleen, raising
serious questions about safety. His next step was to create a heat-inducible
vector protein, so that the gene is expressed only when the tumor is heated.
When the mice were soaked in a water bath for 1 hour at 42 degrees C, he found
that the gene was expressed only in the tumor.
"The mechanism for this response seems to be
complicated," Dr. Li said, "involving the ability of IL-12 to
activate T cells and NK [natural killer] cells, and to inhibit angiogenesis,
while the radiation induces apoptosis or necrosis among tumor cells."