Preclinical trial results read a lot like the script for an old-fashionedWestern movie. The white-hat cohort of mice that got theexperimental drug survived. The black-hat control animals, on acrypto-diet of saline solution, died.
Virologist and gene therapist Milton Taylor, at Indiana University, inBloomington, found himself writing a quite different scenario:"Treatment of a human breast cancer cell line in nude mice with arecombinant adenovirus [AD] containing the human interferonconsensus gene resulted in tumor regression in 100 percent of theanimals."
So far, so similar. But then he continued: "Regression of the tumorwas also observed in controls in which either the wild-type virus or arecombinant virus . . . was used . . . ."
In other words, Taylor's murine model gene therapy trial showed thatthe viral vector not only delivered the interferon gene but on its ownexerted anti-cancer activity, even when transferring a dummy controlgene into the tumor.
To read all about it, see today's Proceedings of the NationalAcademy of Sciences (PNAS), dated April 30, 1996. Taylor's paper,of which he is senior author, bears the title: "Treatment of a humanbreast cancer xenograft with an adenovirus [AD] vector containing aninterferon gene results in rapid regression due to viral oncolysis andgene therapy."
The far-out notion that a human virus might punch lethal holes in ahuman cancer cell isn't all that new. "We've basically rediscoveredthe wheel to some extent," Taylor told BioWorld Today. "The wholeconcept of viral oncolysis first came out about 30 or 40 years ago. Itwas suggested then," he continued, "that this was a means ofmopping up residual tumor cells after surgery _ a very good andreasonable idea."
Taylor himself played a part in that before-its-time idea. "Usingbovine enterovirus," he recalled, "I tried to grow ascites tumors inmice, and noticed that the tumors regressed completely. So weexpanded that experiment to other cancers.
"But none of these," he went on, "were ever followed up, because itwas very difficult to see how to use them clinically. Now there's notthe same fear of using viral vectors that there was 30 or 40 yearsago."
How Does Virus Do It? `No Idea'
What mechanism accounts for the replicating AD's anti-tumor effect,Taylor said, "is not understood. We're trying to look into this somemore, and have very preliminary data, not yet published, whichsuggest that the p53 oncogene is down-regulated by the virus. Whythat should happen, I have no idea."
To be sure, while his replicating virus kills tumors on its own, it doesso much better in harness with consensus interferon.
This is a recombinant composite of the most repetitive amino acids inthe 21 varieties of natural interferon alpha produced in the humanbody. Amgen Inc., of Thousand Oaks, Calif., synthesized this beefed-up version of the antiviral cytokine, which has just completed PhaseIII clinical trials against hepatitis C.
Amgen's director for interferon development is Lawrence Blatt, atthe company's branch in Boulder, Colo. He told BioWorld Today,"We put the synthetic consensus sequence into Escherichia coli hostcells, and produced a molecule with antiviral, antiproliferative andimmunomodulating activity five to ten times higher than any of thenaturally occurring interferons."
Amgen, Blatt said, has been collaborating with Taylor. "We whollyfunded his work, and hold 100 percent of the rights. Certain aspects,"he said, "are patentable; we're exploring that right now."
Since submitting his paper to PNAS last October, Taylor and hisassociates have moved from replicating adenoviral vectors to non-replicating adeno-associated viruses (AAV). "With these new AAVexperiments," he said, "we actually have very similar results, in thathaving Amgen's consensus IFN it seems also to cause inhibition ofbreast cancer."
Taylor made the point that, "The interferon by itself, for some reason,does not cause these cells to grow more slowly." Conversely, "in bothcases, AD and AAV, the virus without the cytokine also has an anti-tumor effect, though not as pronounced as the combination."
Experiments In Smarter Mice, Primates Await Funding
The Indiana scientist would now like to reproduce his experiments inother preclinical model systems, such as syngeneic (geneticallyrelated), immunocompetent mice in place of the immune-deficientnude mice he's used so far. Also, he added, "The group at NCI, theNational Cancer Institute, have actually made transgenic mice thatdevelop breast cancer at the age of three months We're planning _ ifwe can get funding _ to collaborate with them."
Too, there are researchers in Rome who have transplanted the humanimmune system into totally immunodeficient mice. They plan tochallenge them with Taylor's vector system. "All depending onfunding," he observed, "we would collaborate with Rome as well."
He has a grant pending at the National Institutes of Health, "but noidea where it is at the moment."
Taylor's research is no longer getting financial support from Amgen,he said, "although our collaboration continues, because the companyhas been cutting down on its gene-therapy funding in general."
Eventually, if all goes well at the murine level, Taylor and Amgen'sBlatt will both try to go into primates. "Primates are very attractive,"Taylor explained, "because they are closer to the human system,where we have cancer metastases and the development ofspontaneous tumors."
Adenoviral vectors for gene therapy ran into hard times last yearwhen repeated administration of the cystic fibrosis transmembraneconductance gene triggered an immune reaction against AD. (SeeBioWorld Today, Sept. 6, 1995, p. 1.)
Taylor said he doesn't think this menace will rule out AD or AAVvectors for anti-cancer chronic gene therapy. "The presence ofantibodies," he observed, "does not necessarily mean that the virus isgoing to be rejected. After all, people make antibody to HIV, and thevirus can escape that immune response." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.