A natural mechanism pirated by tumors and HIV to evade the immune response is opening the door to better treatment for these conditions, researchers say.
The National Cancer Institute and Iowa biopharmaceutical company NewLink Genetics are pursuing FDA approval to move forward with cancer trials of a drug that inhibits the mechanism, an enzyme called indoleomine 2, 3-dioxegenase, or IDO, says Dr. Andrew Mellor, director of the Immunotherapy Center at the Medical College of Georgia.
He will deliver seminars about the biology and immunology of the mechanism at the Keystone Symposium on "The Potent New Anti-Tumor Immunotherapies," in Alberta, Canada, March 28-April 2 and the World Immune Regulation Meeting April 10-16 in Switzerland.
Immune cells, particularly those in the mucosal surfaces of the gut, lungs and eyes, express IDO to mediate inflammation triggered by the constant assault of substances from outside the body.
Now, scientists know cancer in humans and mice also attract cells that express IDO, which degrades tryptophan, an amino acid essential to survival of immune system orchestrators called T-cells. MCG researchers are still exploring how IDO interacts with other cells to amplify immune suppression.
A team of MCG scientists, led by Dr. Mellor and his colleague, MCG pediatric oncologist Dr. David Munn, showed in 1998 that the fetus also expresses IDO to help avoid rejection by the mother's immune system. When they used an orphan drug known to suppress IDO in pregnant laboratory mice, fetuses were rejected.
The findings, published in Science, led the scientists to suspect and later prove that tumors and some viruses, including HIV, express it as well.
"Cancers should evoke a response from the immune system and don't," says Dr. Mellor. "That is a big question in the immunology field: Why don't they?"
IDO appears to be one reason. "What (cancers) do, we think, is make a protective cocoon so the immune system does not attack the tumor, so that gives you the therapeutic opportunity. If you stop IDO from blocking the response, you should allow the response, so now the specificity of the immune system is brought to bear directly on tumor cells."
Clinical trials, likely to begin this year, will determine whether a slightly modified version of the orphan drug researchers use in the lab, does just that.
NCI has produced kilogram quantities of the IDO inhibitor compound and contracted with a series of labs to do the studies required before studies can move from the laboratory to humans.
"The IDO inhibitor should result, and that is why we need to do the trials because we don't know for sure until we do, in better immunity directed against cancer cells," Dr. Mellor says.
Investigators already have shown that the IDO inhibitor works synergistically with chemotherapy in animal models of cancer. While chemotherapy knocks out some of the immune system's suppressive pathways, the IDO inhibitor prevents cancer cells from tricking the system into ignoring them again.