Specificity of cancer gene therapy vectors increased by more than 1000-fold

By Stephen Pincock

GRONINGEN, The Netherlands (Reuters Health) – American and Dutch researchers have made gene therapy viral vectors up to 10,000 times better at targeting cancer cells, and have received US government funding to conduct human trials with the new vectors this year.

The two phase I trials, both of which should be underway by autumn, will use adenoviral vectors modified to target specific cancer cell markers in patients with glioma or ovarian cancer. One trial is the first using an infectivity-enhanced replicative adenovirus approved by US regulators.

Dr. David T. Curiel, of The University of Alabama at Birmingham, presented details of the approach being undertaken at his lab, the M. D. Anderson Cancer Center and the Free University of Amsterdam, at the 1st International Conference on Clinical Gene Therapy here on Saturday.

"The principle of the work is that efficacy of gene therapy is limited by the lack of specificity of the vector carrying the gene for the appropriate cell type," Dr. Curiel told Reuters Health.

By modifying the structure of the virus' outer coat, the researchers have been able in animal models to show dramatic improvements in targeting "suicide" genes to cancer cells.

"The kinds of gains that we are getting–three and four orders of magnitude, that's a thousand and ten-thousand fold–are really extraordinary," Dr. Curiel said.

"When you develop a new chemotherapeutic agent, if you have something that is two-fold better than the last one, it warrants a human trial. What we're talking about here is that adenoviruses we're using in [gene therapy] trials are 10,000 times less potent than they could be."

The researchers have received funding for two clinical trials using these modified viruses through the National Institutes of Health's Rapid Access to Intervention Development (RAID) program.

The researchers believe that using a conditionally replicative virus, as they will in one of the trials, should improve the efficacy of treatment.

Most gene therapies currently under investigation for cancer use non-replicating virus. But a limit of this approach is that not all tumor cells become infected with the virus, and killing all the tumor cells relies on neighboring cells being killed by toxins released from infected cells, called the "bystander" effect.

"But…we recognized that the bystander effect wasn't sufficient, so replicative systems are the next level of conceptual intervention…where a small infectious inoculum can amplify," Dr. Curiel said.

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