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Natural Mechanism For Immune Suppression Paves Way For Cancer Trials

Date:
March 29, 2007
Source:
Medical College of Georgia
Summary:
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.
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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.”


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Materials provided by Medical College of Georgia. Note: Content may be edited for style and length.


Cite This Page:

Medical College of Georgia. "Natural Mechanism For Immune Suppression Paves Way For Cancer Trials." ScienceDaily. ScienceDaily, 29 March 2007. <www.sciencedaily.com/releases/2007/03/070328111021.htm>.
Medical College of Georgia. (2007, March 29). Natural Mechanism For Immune Suppression Paves Way For Cancer Trials. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2007/03/070328111021.htm
Medical College of Georgia. "Natural Mechanism For Immune Suppression Paves Way For Cancer Trials." ScienceDaily. www.sciencedaily.com/releases/2007/03/070328111021.htm (accessed May 23, 2017).

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