By Dean Haycock
Special to BioWorld Today
Individually, bacterial toxins and brain tumors produce suffering and despair. Together they may offer something considerably more positive. Already, toxin treatment has produced complete remission of transplanted human brain tumors in mice. Clinical trials may soon determine if human cancer patients respond as well.
Preclinical data showing the effectiveness of immunotoxin therapy appears in "Complete Regression of Established Human Glioblastoma Tumor Xenograft by Interleukin-4 Therapy," a paper in the Aug. 15 issue of Cancer Research. Scientists from the FDA and the National Cancer Institute, in Bethesda, Md., took advantage of the presence of specific proteins on brain tumor cells to treat in mice what is now essentially untreatable in humans. Non-malignant cells in the brain do not express these proteins, which bind a cytokine called interleukin-4 (IL-4). To exploit the differential expression of this cancer cell marker, they used a hybrid molecule called a fusion toxin.
"It will only bind the cell if it has IL-4 receptors," said co-author Raj Puri, chief of the laboratory of molecular tumor biology at the Center for Biologics Evaluation and Research, a part of the FDA. Puri collaborated with Ira Pastan of the Laboratory of Molecular Biology at the National Institutes of Health (NIH) on the study.
This fusion toxin consists of three "working" domains. The first domain is made of part of the IL-4 molecule. The other domains are derived from Pseudomonas exotoxin (PE). In the words of the trade, the fusion toxin is a bifunctional protein consisting of a cancer cell specific recognition domain and an enzymatic toxin domain. That means the IL-4 part, the first domain, gets the fusion toxin as far as the receptor.
The cell then brings the drug inside by endocytosis. The second domain allows the fusion toxin to make it further into the cell. There, the toxin is cleaved by a cellular enzyme and the third domain is activated. The toxin then goes to work by shutting down protein synthesis in the cancer cell, which dies.
Previous work showed the fusion toxin binds to cancer cells with high affinity and kills them in test tubes. The latest paper shows the IL-4 toxin works in whole animals. The experimenters implanted human malignant glioblastoma cells under the skin of "nude" mice, which lack the ability to reject the foreign tissue implants.
There is no cure for malignant glioblastoma. This type of cancer is among the most deadly of those derived from glia cells, the "other" brain cells that perform many supporting functions for neurons. Glioblastomas account for more than one-third of the 17,500 primary malignant tumors that affect American citizens every year.
Mice Brain Tumors To Be Studied Next
In one phase of the animal study, injection of fusion toxin directly into large tumors (60 cubic millimeters) every other day for a week or so produced complete remission in all six mice. The mice remained tumor-free for 100 days. The treatment produced no observable toxicity. Less complete, but nevertheless still impressive, results were obtained when the fusion toxin was delivered intravenously or into the abdominal cavity.
To simulate human disease more closely, the researchers next will study the effect of the fusion toxin on tumors growing directly on the brains of mice instead of under the skin.
Neurocrine Biosciences Inc., of San Diego, obtained exclusive worldwide rights to IL-4 fusion toxin from the NIH in May. The drug is being infused into brain tumors in 11 patients at the John Wayne Cancer Institute, in Santa Monica, Calif. Neurocrine hopes to begin expanded Phase I/II trials at eight centers in the U.S. and Europe very soon.
Michael Berger, professor and chairman of neurosurgery and director of the Brain Tumor Research Center at the University of California, in San Francisco, is one of those who will test the drug in the clinic.
"This is a completely new and radically different approach," Berger said. "It is very exciting." The experimental drug will be delivered directly into brain tumors by means of catheters, allowing continuous infusion. This procedure bypasses the blood-brain barrier, which prevents many compounds from entering the brain, and allows high concentrations of drug to be delivered on target. Not only the tumor, but a zone around the tumor that might contain undetectable cancer cells can be saturated with drug delivered in this way.
"We are hoping that with the eight centers involved and all of them being very experienced brain tumor centers, patients can be enrolled in about three months, and that we will have results three or four months thereafter," said Stephen Marcus, senior vice president of clinical and regulatory affairs and chief medical officer of Neurocrine.
The high potency of the compound in the preclinical studies suggests to Marcus there is a heightened chance of seeing good efficacy in the early-phase clinical trials.
Puri and his colleagues have also detected IL-4 receptors in malignant melanoma, AIDS-associated Kaposi's sarcoma and cancers of the breast, ovary, kidney, prostate and head and neck. The FDA and NIH researchers are now performing experiments in an in vivo AIDS-associated Kaposi's sarcoma model, a breast tumor model and an ovarian tumor model.
"We are a neuroscience company, so our intense focus is on defining the activity in malignant brain tumors and aggressively bringing this to the marketplace as quickly as we can," Marcus told BioWorld Today. "But having said that, we are of course interested in the other data and will be continuing to discuss that with Drs. Puri, Pastan and others." *