|
Dr. Andrew Mellor, director of
the Immunotherapy Center at the Medical College of Georgia.
Photo: Medical College of Georgia |
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." |
