Ad blockers pt 3

Previously:

• Part 1
• Part 2

In 1993, Jack Roth's group described the adenovirus p53 vector that would become Advexin in a short paper in the journal Biotechniques. The earliest clinical trials in the gene therapy trials database with p53-carrying Adenovirus vectors started in 1995, with Jack Roth as one of the PIs. Overall, the database lists 34 US clinical trials of Adenovirus vectors carrying p53 for cancer therapy. Some of these may have involved Introgen competitors, but many were for what would become known as Advexin. A 1997 press release describes the results of one set of Phase 1 trials, and a collaboration:

Introgen Therapeutics, Inc., an Austin-based company engaged in the development of cancer therapeutics, sponsors Drs. Roth and Clayman along with 25 other clinicians and researchers at M.D. Anderson Cancer Center. Introgen and RPR Gencell, the gene therapy division of Rhone-Poulenc Rorer, are collaborating to develop and commercialize gene therapy products based on the p53 pathway and k-ras oncogene inhibition.

Adenovirus vectors fell under a cloud in 1999 when an Arizona teenager died during clinical trial involving adenovirus vectors. This was not a trial involving Introgen, but all ad vectors were suspect. Even improved vectors were cause for worries:

Gene therapy researchers at the Baylor College of Medicine in Houston, Texas, who recently reported success with the 'gutless' adenoviral vector in animals may not get to test the vector in humans.

The pharmaceutical company, Merck, which owns the licence on a technique used to produce the vector, is refusing to extend its material transfer agreement (MTA) with Baylor, saying that it does not want to be liable for any problems the vector might cause in clinical trials.

How this affected the Introgen Adenovirus projects is not clear. Phase 1 and Phase 2 trials continued, and Introgen-sponsored scientists presented safety results at meetings. In 2002, the Ad5-p53 vector was trademarked as Advexin, and Introgen was telling the world to expect an approval application in 2004 (Biodrugs 17 (3): 216-222). Also from that review:

In April 2001, Aventis Gencell and Introgen restructured their existing collaboration agreement for p53 gene therapy products. Aventis Gencell indicated that p53 research had suffered from internal competition for resources and was pulling back from its development agreement with Introgen for p53 gene therapy products.

In a 2004 review of gene therapy skepticism about the Advexin approach appeared:

Results published to date have been disappointing. Phase I trials for recurrent glioma reported only modest survival benefit and expression of adenoviral derived p53 only a short distance from the site of virus administration.¹¹⁵ Phase II/III trials for ovarian cancer failed to show treatment benefit with intraperitoneal administration of adenovirus expressing p53 with chemotherapy after debulking surgery.¹²⁰ Finally, Swisher et al published antitumour effects associated with the treatment of non-small cell lung cancer; however, no comparable control group was described in their report.¹¹⁶

That last bit is harsh. The author is not just saying the results were disappointing; he's calling the quality of the studies into question.

The potbanging would get worse.

To be continued...