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Liver an Excellent Target For Cancer Gene Therapy

pped gene therapy research and spawned widespread safety concerns about gene therapy involving the liver.

“At that time, I was treating patients with colon cancer that had spread to the liver using a very similar adenoviral vector administered in exactly the same way – direct infusion into the main artery feeding the liver,” said Reid, who is now an associate professor of clinical medicine in the UCSD School of Medicine. “We saw virtually no problems with toxicity in 35 study participants who received a total of nearly 200 infusions across several study sites.”

So Reid and colleagues carefully re-analyzed the data from the 17 participants from the Stanford site to determine the impact of repeated adenoviral exposure on liver function, and documented that there were no significant problems. While the analysis was not designed to demonstrate impact on disease, it showed that seven of the 17 patients had stable-to-improving disease at the completion of four viral infusions. The researchers then demonstrated that normal liver cells could not be infected with an adenovirus, which led them to investigate where the receptor was located. They found it hiding at the junction between liver cells and proved that it was inaccessible from the blood flow in the liver. From there they showed that cancer cells had lost structural polarity, resulting in random distribution of CAR receptors on their surface, thereby allowing the virus to attach to and infect the tumor cells.

“In the process of proving that liver toxicity is not an issue in gene therapy, we have also shown that cancer cells metastatic to the liver are a perfect target for gene therapy because the cancer cells, but not the normal liver cells, are infected by the adenoviral vector,” said Reid. “We also found that other cancer cells, including those from the breast, pancreas and prostate, are readily infected by adenoviral vectors indicating disorganized expression of the CAR receptor
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