Promising experiments seek ways to stop cells from attacking skin,
organs
updated 2:44 p.m. ET, Mon., Nov. 12, 2007
WASHINGTON - Bone marrow transplants are one of cancer care's
striking successes, but they have a dark side: The transplanted cells
can turn on patients, attacking their skin and organs.
The potentially deadly side effect with the unwieldy name of graft-
versus-host disease, or GVHD, strikes several thousand each year. The
last decade has brought little progress in battling it.
Last month brought another blow, as the Food and Drug Administration
rejected the new drug closest to market.
But that drug, called orBec, isn't dead; its manufacturer is pledging
additional research to satisfy FDA's concerns. And it joins a list of
other promising experiments into ways to ease the misery — from novel
stem-cell infusions to drugs that block immune cells-run-amok.
The burst of research comes none too soon, as a long-lasting form of
GVHD is on the rise.
Longing for an alternative
"I love my doctors, but they throw up their hands. They don't know
what to do," laments Stephen Dugan, 54, of Radnor, Pa., who longs for
an alternative to the problematic steroid that is today's treatment
mainstay.
His transplant four years ago saved Dugan from cancer. But two months
later he barely survived a harsh bout of GVHD; now he battles a less
severe but chronic form of the disease.
When someone receives a transplanted organ, the big fear is that
their own immune system will attack the new "foreign" tissue. GVHD is
the opposite problem. It occurs when patients receive donated bone
marrow or the stem cells that produce it, pieces of someone else's
immune system. Sometimes the donor's T cells, whose job is to hunt
foreign invaders, become super-aggressive and attack the recipient's
body.
It happens in at least half of the more than 6,000 Americans who
receive allogeneic — or donated — marrow or stem-cell transplants
every year. Many times, GVHD is mild or moderate, causing skin rashes
or blistering, vomiting, liver or lung damage. But one of every five
cases is life-threatening. A particularly dangerous form ravages the
stomach and intestines, causing unremitting vomiting and diarrhea.
The only treatment: Super-high doses of the steroid prednisone for
weeks, to suppress out-of-control immune cells and the inflammation
they cause. But the treatment's side effects are severe, even deadly:
Patients fall prey to infections; it debilitates bone and muscle
until some become bedridden; and it can cause violent mood swings.
Plus, about half of seriously ill patients fail to improve, prompting
doctors to frantically add other steroids.
"They're our best friends but our greatest enemies," is how Dr.
Steven Pavletic of the National Institutes of Health describes
prednisone and its cousins.
Now in advanced testing are treatments that aim to calm GVHD without
that body-wide steroid toxicity:
OrBec is a milder kind of steroid, a pill version of the
beclomethasone that asthma patients have long inhaled. Dr. George
McDonald of Seattle's Fred Hutchinson Cancer Research Center
reformulated the drug to coat the gastrointestinal tract, not roam
the body.
Adding orBec to standard prednisone seemed to improve survival, a
year after gut GVHD first struck, by 45 percent. But because of a
statistical issue with the research, the FDA told Dor BioPharma to
show more evidence that orBec works. The company pledged to do so,
and already has a different Phase III trial under way — to see if
giving orBec with the transplant can prevent gut GVHD in the first
place.
The experimental drug Prochymal aims to soothe the source of GVHD's
inflammation without suppressing immunity. It's made of a different
kind of stem cell, mesenchymal cells. Your own mesenchymal cells are
damaged during a bone marrow transplant. But when donated ones are
infused into patients' bodies, they steer to wherever GVHD is
attacking. There, overly aggressive T cells spur high levels of
chemicals called cytokines that in turn inflame tissue.
The mesenchymal cells "change the chemical environment and basically
put the brakes on" that damaging process, explains Dr. Hans
Klingemann, bone marrow transplant chief at Tufts New England Medical
Center. He is the independent safety monitor for Osiris Therapeutics'
studies of the drug.
In a small study, adding Prochymal to steroid treatment doubled the
chances of a complete recovery. Now a large Phase III trial is
beginning to try to prove that effect.
Johns Hopkins University researchers are studying if two doses of an
old cancer drug, cyclophosphamide, at the time of transplant could
prevent GVHD anywhere in the body. It's a drug thought to block the
function of only bad-acting immune cells, while allowing the rest of
the immune system to build back up after the transplant. Of roughly
100 patients tested so far, 65 percent have needed no further anti-
GVHD protection, says Dr. Leo Luznik of Hopkins Kimmel Cancer Center.
Larger studies at other hospitals are about to begin.
© 2007 The Associated Press. All rights reserved. This material may
not be published, broadcast, rewritten or redistributed.
http://www.msnbc.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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