Natural mechanism for immune suppression may lead to new cancer drugs

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.

"Chemotherapy is toxic to cancer cells, but the problem is the cells come back so you don't completely eradicate the tumor. One of the main reasons they come back is the tumor already has established an environment which helps protect it, even after chemotherapy," Dr. Mellor says.

Although the IDO inhibitor will first be studied alone, he believes it will become part of the treatment cocktails that are becoming the standard for cancer care, possibly enabling less toxic doses of other drugs to be used.

Another goal for IDO suppression is to treat chronic infections that induce this mechanism, Dr. Mellor says.

"This mechanism is induced by pathogens to protect themselves from host immunity," says Dr. Mellor. "HIV certainly is a potent inducer of this mechanism." He suspects other diligent viruses and bacteria are as well.

"This is obviously an evolutionary adaptation that the pathogen has to protect it from being eliminated by the host," he says. "That is why the infection does not go away. In the case of HIV, we know it persists for decades, and in those decades it's slowly eating away at the immune system so that it becomes unable to deal with the infection. That is where AIDS comes from. The current standard of care for HIV patients is to slow that process, that wearing-down process of the immune system."

In 2002, MCG researchers showed that dendritic cells, which present antigens to T cells, express IDO. "If they express IDO, it's an important control point," Dr. Mellor says of research published in the Sept. 13, 2002 issue of Science.

"IDO has been known for decades," he says. "What was not known was IDO activity was regulating the adaptive immune response."