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Report:
License to kill
Investigator: Cornelis
Melief
Thursday
Jul 26th, 2001
by Julie Clayton
New data from animal studies suggests that
opposition from the host immune system could hinder the success of the
numerous cancer vaccines currently in clinical trials. But a solution is
at hand, said researchers today.
Kees Melief and his team at the University of Leiden have built a
strong reputation for their research into vaccines against melanoma.
While clinical trials are now underway based on their research, Melief
continues to work on ways to improve the vaccine strategy.
"Five years ago people were laughing at us, but now [cancer
vaccines] are becoming a reality," Melief told BioMedNet News.
One possibility, which will soon be tested in humans, is the idea of
boosting the effectiveness of dendritic cells (DCs), which cancer-killing
T cells need to help spark their lethal activity. So far in mice, this
involves injecting an antibody to a DC receptor called CD40, which makes
DCs stimulate killer T cells more strongly. As a result, the killer T
cells are more effective at eradicating experimental tumors.
CD40 is, in Melief's view, a "license to kill" receptor.
Rather than simply injecting the antibody into the blood stream, the best
site of injection is directly into the tumors. DCs are present in tumors,
but inactive until the antibody is injected.
"This is an interesting type of treatment to be tried for human
cancer," he told delegates this morning.
Melief then revealed that a chance observation has led to another
procedure that may boost cancer immunity. His team had been examining the
effectiveness of a vaccine against melanoma in mice, and were testing the
relative contributions of different subsets of T cells to the immune
response.
By selectively removing subsets using antibodies, Melief's Ph.D.
student, Roger Sutmuller, saw a curious anomaly. When the killer T cell
subset was removed, there was no longer an effective immune response
against the tumors, and the mice died as expected. But when another T
cell subset, with the receptor CD4, was removed, the mice were completely
cured of the disease. The team had assumed that removing the CD4 cells
would have no effect.
Probing further, they discovered that it was removal of a minority of
CD4 T cells, bearing a receptor called CD25, which boosted the immune
response to tumors. This, says Melief, suggests that the CD25 T cells are
normally acting in opposition to attempts by CD8 T cells to eradicate
tumors. In effect, they are helping the tumors fight off the host's
immune response.
"At all stages, removal of these CD25 suppressor cells is
beneficial," said Melief. He then added that the exception to this
was immediately after vaccination, when many more T cells would
temporarily carry the same CD25 receptor.
CD25-bearing T cells, also known as "regulatory T cells",
are thought to exist in humans, but their role in any immune response is
not clear.
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