A research team at Columbia University has designed a novel viral-based gene therapy they say blasts through a body, targeting both primary and distant tumors, while leaving normal cells untouched. In the 15 mice they tested, injections of the therapy in tumors on one side of the mouse eliminated those cancers as well as tumors on the other side of the animal’s body, producing a cure in all of the mice.
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“The beauty of this approach is that two methods are being used to destroy a tumor,” said Devanand Sarkar, M.B.B.S, Ph.D., the study’s primary author, associate research scientist at Columbia. “The virus we designed replicates within a tumor, and at the same time produces a massive amount of a cancer killing compound. Either action alone is damaging and potentially deadly, but together they are lethal.”
Columbia researchers built the therapy around their earlier, pivotal discovery of a cytokine (a signaling protein) called melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). A technology developed in the Fisher laboratory, “subtraction hybridization,” applied to human melanoma, induced the cancer to revert to a more normal state, allowing comparison of genes expressed in both states. They discovered mda-7/IL-24 was progressively down-regulated as melanoma developed. In its normal state, the cytokine may affect growth and immune regulation, whereas expression at high levels kills cancer cells.
The investigators altered an adenovirus to carry the mda-7/IL-24 into tumors that normally did not express the gene, and based on successful animal studies, this cytokine was tested for safety in patients with advanced melanoma and other solid cancers. “Interestingly, this phase I clinical trial produced a significant clinical response,” Fisher said.
To make the treatment more potent, they then paired the mda-7/IL-24 gene with a “replication competent” adenovirus, a virus that can multiply within cells. After such a microbe enters a cell, it can reproduce and cause the cell to burst, releasing more viral particles. During replication, the mda/IL-24 gene is also reproduced and then expressed, delivering huge quantities of active mda/IL-24 locally and systemically.
Finally, the researchers worked out a strategy to ensure that the loaded virus would only replicate within cancer cells. They manipulated the viral genome again, and substituted its normal promoter (E1A) with a promoter (PEG-3) that they discovered could only be activated by transcription factors found in cancer cells. That means that if the virus may enter a normal cell, it won’t replicate and the cell will not die, the researchers say. It also suggests that the therapy will work in a variety of cancers “because virtually all cancers we have tested contain the necessary transcription factors that activate the PEG-3 promoter,” Fisher said.