Originally created 09/09/01

Cancer researchers study tumor-protecting enzyme



Puzzling out one age-old mystery at Medical College of Georgia may lead researchers to solve another: how cancerous tumors evade the body's immune system.

Researcher David Munn and colleagues Andrew Mellor and Simon Conway had isolated a system a few years ago by which the fetus was able to locally disable the mother's immune system and keep it from rejecting the fetus. They zeroed in on an enzyme known as indoleamine 2.3-dioxygenase, or IDO, which degrades tryptophan, essential for the survival of T-cells in the immune system.

Now, Dr. Munn said, it seems tumors are doing the same thing, using the same enzyme. A drug that can knock out the enzyme is being tested on cancers in mice. If effective, it may be developed for human clinical trials with the aid of the National Cancer Institute.

The MCG researchers set the scientific world abuzz in 1998 when they published a paper in the journal Science detailing a simple yet elegant system for what had long puzzled scientists - why the fetus, with foreign genetic material from the father, was not attacked by the mother's immune system. They tested the IDO theory by using a drug to block it, and that resulted in the fetus being rejected. The system was further detailed in the December issue of Nature Immunology.

The MCG team has long suspected that the same enzyme system may be involved in other areas of the body to provide tolerance when the immune system should not kick in, as with pregnancy.

"This is part of the fundamental underlying mechanism by which the immune system keeps itself from responding excessively and inappropriately to innocuous and nonharmful substances," Dr. Munn speculated. One popular theory, called the immune surveillance theory, holds that the immune system is constantly finding and eliminating tumors from the body that never come to our attention.

"The only ones that are successful, i.e. they come to clinical attention and are going to kill their hosts, are the ones that have evolved a way, have adapted themselves to evade the immune system," Dr. Munn said.

So the MCG team has turned to the same drug they used to turn off IDO in testing their theory about the fetuses as a way to potentially turn it off with tumors and bring them to the attention of the immune system. The drug is in the public domain, and drug companies could not get a patent on it, so MCG is working the orphan drug program of the National Cancer Institute to potentially develop it as a cancer-fighter.

"If we can convince (the institute) that this is a safe and effective drug in the process we've got planned out for the next six to 12 months, then at that point we will propose that they make the drug as if they were a drug company, that they make a supply of the drug for the Phase I clinical trials," Dr. Munn said.

The researchers are working with clinical collaborators Russell Burgess, the chief of medical oncology at MCG, and Jeffrey Lee, the chief of pathology at the Augusta Department of Veterans Affairs Medical Centers, to get access to human tissue samples.

Immunotherapy was a hot theory for fighting cancer in the '70s but lost favor in the '80s when some therapies didn't pan out. Now it is back, said Trent Spencer, a researcher at the University of South Carolina in Columbia who is working with gene therapy and immunotherapy to fight cancer. Dr. Spencer is trying to insert a gene in immune system cells to confer on them resistance to chemotherapy drugs and allow them to survive chemotherapy and help the drugs battle the tumor.

The IDO enzyme MCG is focusing on is one of several that scientists are targeting in hopes of bringing the immune system back into play, Dr. Spencer said.

"Once they start to be able to induce the immune system into fighting the tumor, then we can come in and use some of the therapy we're developing around the immunotherapy idea," Dr. Spencer said.

The idea of using the body's own system has tremendous appeal right now, Dr. Spencer said.

"It's very hot," Dr. Spencer said. "It's my opinion that immunotherapy is the next advancement in cancer treatment. At least I'd like to think so; it has tons of potential. Is immunotherapy it or not? Time will tell."

Reach Tom Corwin at (706) 823-3213 or tomc@augustachronicle.com.



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