When a cancerous tumor takes hold in the body, it begins a sinister process of shutting down the host's immune system at the site. One of the mechanisms that tumors use to accomplish this shutdown -- IDO-- has been the focus of study by researchers at the Medical College of Georgia for the past decade.
Now, a drug that suppresses that very mechanism is moving into clinical cancer trials - a development that has direct ties to MCG's work.
The FDA has approved early clinical trials of the drug, 1MT, for patients with lung and other tumors at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla. MCG is now pursuing FDA approval of additional clinical trials to combine the new drug with chemotherapy in breast cancer patients
The ability of tumors to suppress the immune system has been the subject of years of study by Dr. Andrew Mellor, GRA Eminent Scholar and director of the Immunotherapy Center at MCG, and his colleague Dr. David Munn, a pediatric hematologist/oncologist and director of the Cancer Immunotherapy Program at the MCG Cancer Center.
In the August 2007 issue of The Journal of Clinical Investigation, the researchers published their latest findings. They showed that one way IDO helps tumors fly under the radar of the immune system is by stimulating powerful regulatory T cells that turn down the immune response. It was known that tumors assemble a protective barrier of these regulatory T cells, or Tregs, but how they do this was an unknown.
“People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body,” Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue. “The number doesn’t change a lot, but their activation state changes hugely.”
Dr. Mellor and Dr. Munn think that the IDO inhibitor 1MT, when used in combination with chemotherapy, can help eliminate the tumor’s ability to suppress the immune response based on extensive pre-clinical studies in mouse models of tumor development.
IDO is part of the body’s natural immune system function. 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.
A team of MCG scientists, led by Dr. Mellor and Dr. Munn, showed in 1998 that a developing fetus also expresses IDO to help avoid rejection by the mother’s immune system. When they used 1MT in pregnant laboratory mice, fetuses were rejected.
The findings, published in Science, led the scientists to suspect that tumors and some viruses, including HIV, exploit IDO 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.”
“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.
He believes the IDO inhibitor 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 persistent 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 that IDO activity was regulating the adaptive immune response.”
Story by Toni Baker with photo by Phil Jones
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