BETHESDA, Md. -- No one knows why many types of cancer cells produce copious quantities of insulin-like growth factor (IGF-1) compared with normal cells, Joseph Ilan told BioWorld. But he is betting that suppressing IGF-1 synthesis and performing some additional manipulations could destroy brain tumors.
On Tuesday, the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health approved the Case Western Reserve University School of Medicine biologist's protocol to treat patients with gliomas that overexpress IGF-1 by a 19-0 vote, with no abstentions. "This was a fascinating protocol," said Leonard Post, vice president of experimental therapy for the Parke-Davis Pharmaceutical Division.
The RAC members were impressed with Ilan's animal data; his technique had cleared glioblastomas from all 30 of the rats tested.
Following the introduction of antisense IGF-1 cDNA into the rat gliomal cells, IGF-1 mRNA and protein levels plummeted. Next, the researchers irradiated the transfected tumor cells to kill them, and injected the cells subcutaneously into the rats. For reasons not yet understood, the injected tumor cells induced CD T lymphocytes to destroy the tumor cells, which previously had been invisible to the host's immune system, Ilan told BioWorld.
In mouse studies, tumors regressed in three to four weeks following injection of antisensec DNA-treated, irradiated tumor cells. "We concluded that the IGF-1 antisense strategy may reverse a phenotype which allows C6 glioma cells to evade immune surveillance," wrote Gary Nabel, professor of internal medicine and biological chemistry at the University of Michigan Medical Center and associate investigator at Howard Hughes Medical Institute, in his protocol.
Preventing the Spread of HIV.
One of Monday's highlights was the first approval of a direct anti-viral therapy, by a vote of 14-0 with four abstentions. The therapy is designed to prevent the spread of HIV in infected people.
The scientific mechanism is straightforward. The retroviral protein, Rev, is necessary for viral replication, as it regulates transport of viral RNA from the nucleus into the cytoplasm. It binds to an RNA sequence in the virus called the Rev responsive element.
Principal investigator Nabel proposed to block the Rev protein's access to the element. A mutant form of the Rev gene, Rev M10, binds to the Rev responsive element without recruiting the cellular factors that mediate export of viral RNA. "It's kind of like trying to unlock your car door when someone has broken a key off in the lock," said Nabel.
"We have taken T cells from patients and put the gene in," Nabel told BioWorld. "The purpose of the study is to give those cells back to the patient." If the T cells with the mutant form of Rev survive in the patients in greater numbers than in those without it, "that will tell us they are going to be protective." And if so, the ultimate goal would be to install the mutant Rev gene in stem cells, Nabel said. The technique would be beneficial if it slowed viral replication enough to preserve a functional immune system.
The vector is a murine virus, which has raised concerns about the possibility that promiscuity among HIV-positive people might broaden the virus' infectivity. But RAC members thought such risks were small. Nonetheless, Nabel is collaborating with Vical Inc. of San Diego, Calif., on a cationicliposome that might substitute for the murine virus, eliminating this risk. 060993IGF-1
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.