Antisense gene therapy is about to take on a brain cancer that defiessurgery, defeats radiation, frustrates chemotherapy and _ so far _subverts its host's immune system.
The malignancy is glioblastoma multiforme, an incurable tumor ofthe brain's glial cells, which strikes some 8,000 Americans annually,and kills three-fourths of them within a year of diagnosis.
Surgical removal of the tumor rarely if ever catches every lastmalignant cell, and those that escape the surgeon swiftly grow back.
For years, immuno-oncologists wondered how tumor cells in generalcontrived to escape the immune system's notice. Now they know.
Within the past half-decade, researchers discovered thatglioblastomas, like other epithelial cells, secrete a transforminggrowth factor (TGF-b) that emasculates the body's cellular andhumoral immune defenses before they have a chance to turn on _i.e., get activated.
Now, scientists at the Sidney Kimmel Cancer Center, in San Diego,have devised and tested an antisense genetic construct that switchesoff the glial cells' TGF-b before it has a chance to hit those immunedefenses. In rats, the customary model for brain research, they scored100 percent extirpation of residual tumor cells.
Neurosurgeons at the University of California, Los Angeles (UCLA),plan Phase I clinical trials of the antisense approach this summer. Itsprincipal developer, gene therapist and cell biologist Habib Fakhrai,said Monday the Recombinant-DNA Advisory Committee to theNational Institutes of Health already has granted permission for thehuman study, which now awaits FDA approval.
Richard Bartholomew, co-director of cancer studies at ImmuneResponse Corp., of Carlsbad, Calif., licensee of Kimmel's patent-pending new technology, told BioWorld Today that his companyexpects to extend the antisense modality to gene therapy for colonand prostate cancer "by the end of this year."
Fakhrai is first author of a paper in today's Proceedings of theNational Academy of Sciences (PNAS). Its self-explanatory title:"Eradication of established intracranial rat gliomas by transforminggrowth factor b antisense gene therapy."
A co-author is neurosurgeon Keith Black at UCLA. Fakhrai has justleft Kimmel to join him there as co-principal investigator, to carry outthe impending Phase I trial. The paper's senior author, medicaloncologist Richard Sobol, directs clinical science at the KimmelInstitute. He told BioWorld Today that the safety study expects toenroll 15 to 20 brain cancer patients, just after surgical resection oftheir primary glioma, and before the tumor has had a chance to growback.
As described in PNAS, the Kimmel team surgically implanted 5,000rat gliosarcoma cells into the forebrains of two dozen healthy rodents.This is six times the number that kills 99 percent of its recipientswithin five weeks.
Five days later, they inoculated 18 of the rodents with a gene therapypackage containing similar gliosarcoma cells that incorporated 870nucleotide bases of a simian TGFb gene turned front to back.
When this antisense sequence came up against the RNA busilytranscribing the immune-suppressing TGFb, it shut down, leaving theimmune system free to counterattack the tumor cells. Which it didwith a vengeance:
* All 18 of the rats that received the antisense gene fragment survivedfor 12 weeks, and their brains showed no residual trace of themalignant gliosarcoma cells.
* Nine of the 12-week survivors then received injections of 100,000or 1 million malignant cells; all of the former were still alive sixmonths later.
* Meanwhile, from 80 percent to 100 percent of various rat controlcohorts succumbed to non-antisense formulations, ranging fromsaline solution to untreated glial sarcoma cells.
* A separate antisense study against ovarian cancer cells awaitspublication. Sobol said results were equally favorable.
Immunologist Ivor Royston, president and CEO of the KimmelCenter, said that thanks to "Dr. Fakhrai's genetic engineeringtechniques of putting a gene in, which switches the expression of thisTGF-b blocking factor, now all of a sudden the immune systembecomes very potent, and eradicates the tumors in all of the animals."n
Royston concluded: "So it is a major breakthrough, and lendscredence to the idea that, yes, the immune system will recognizecancer cells as being foreign, and will eliminate them." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.