Graft versus Host Disease

Graft-versus-host disease (GVHD) is a
common complication of allogeneic
(taken from others in the same
species) bone marrow transplantation
in which functional immune cells in the
transplanted marrow recognize the
recipient as "foreign" and mount an
immunologic attack. It can also take
place in a blood transfusion under
certain circumstances.
Approximately 6300 patients receive
allogeneic hematopoietic stem cell
transplants in the United States each
year. Nearly 50% (approximately
3,150) of these patients develop acute
GVHD. A fraction of these patients
(approximately 870) will progress to
the severe stages of the disease.
Thus, roughly 350 patients each year
face tremendous odds against survival.
Development of new therapeutic
agents and strategies to rescue
patients with steroid refractory, acute
GVHD would provide a significant
benefit in an area of unmet medical

Patients who are lucky enough to get a
transplant for a failed organ usually
face a lifetime on anti-rejection drugs,
which are expensive, dangerous and
not always effective.

But in the future, those drugs may not
be needed. A small new study
suggests that patients receiving an
organ that is  less than a perfect match
can be protected against rejection by a
second transplant — this time of the
organ donor's stem cells.

In a small study, announced in March
2012, kidney transplant patients given
a mixture of stem cells from their organ
donor were able to quit taking anti-
rejection medicine, suggesting that life-
long reliance on the toxic drugs may
be avoidable.

Five of eight patients treated were able
to stop taking about a dozen pills a day
to suppress their immune systems.
The drugs, which prevent rejection and
stop tissue from a donated kidney from
attacking the patient, can damage the
transplant and cause diabetes,
infections, heart disease and cancer.

In the breakthrough they   mixed stem
cells from the donor’s infection-fighting
immune system with the patient’s
natural immune system. The result
enabled tissue from both to co-exist in
the transplant patient without either
being seen as “foreign” by the immune
system, researchers said.

The results “may potentially have an
enormous, paradigm- shifting impact
on solid-organ transplantation.

The findings are particularly striking
since the patients weren’t perfect
tissue matches with the living donors.
The mismatch traditionally makes it
more difficult for the donated organ to
survive since the patient’s immune
system perceives the unfamiliar tissue
as a threat.

The findings are particularly striking
since the patients weren’t perfect
tissue matches with the living donors.
The mismatch traditionally makes it
more difficult for the donated organ to
survive since the patient’s immune
system perceives the unfamiliar tissue
as a threat.

Two of the study’s 10 authors are
officers in Regenerex LLC, a startup
biotechnology company based in
Louisville, Kentucky, that is involved in
processing the donor cells.  Suzanne
Ildstad, director of the Institute of
Cellular Therapeutics at the University
of Louisville in Kentucky  has an equity
interest in the company and is an
author on a patent for the facilitator
cells, which she discovered.

The strategy could offer hope, too, for
patients receiving bone marrow
transplants to treat blood cancers,
speeding the process of finding a
donor by allowing physicians to use
stem cells that today would be rejected
as incompatible.

In June 2011 the FDA has approved
belatacept (Nulojix) from Bristol-Myers
Squibb for use with other
immunosuppressants in preventing
organ rejection in kidney transplant

The drug -- a selective T-cell
costimulation blocker -- is given in 30-
minute intravenous infusions.

Drug approval was based on two
phase III clinical trials of 1,200 patients
comparing belatacept against

Belatacept was approved with a boxed
warning for an increased risk of post-
transplant lymphoproliferative disorder.

A second boxed warning -- common to
all immunosuppressants -- cautions of
an increased risk of serious infection
and other cancers.

Adverse events during the trials
included anemia, constipation, kidney
or bladder infection, and swollen legs,
ankles, and feet.

Belatacept was developed by Bristol-
Myers Squibb to prevent graft rejection
and maintain kidney function following
kidney transplant.

Belatacept is a fusion protein designed
to bind to a specific site on certain
cells of the immune system (i.e.,
antigen presenting cells) to block the
second signal necessary to activate  T-
cells, which coordinate immune-
mediated rejection of transplanted

"Finally, the drought of new agents in
transplantation is over," said Flavio
Vincenti, MD, professor in the Division
of Nephrology at the University of
California–San Francisco. "The FDA
approval of belatacept means that
transplant patients will have an
additional choice in
immunosuppression, and especially
with a drug that preserves renal
function and has the potential to
prolong the life of the graft," he said.

Soligenix's lead product, orBec (oral
beclomethasone dipropionate or BDP),
is a potent, locally acting corticosteroid
being developed for the treatment of
acute gastrointestinal Graft-versus-
Host-Disease (GI GVHD), a common
and potentially life-threatening
complication of hematopoietic cell
transplantation. orBec is currently the
subject of a confirmatory Phase 3
clinical trial for the treatment of acute
GI GVHD and an NIH-supported.

Australian regenerative medicine
company, Mesoblast Limited  
announced that based on positive
results from its bone marrow transplant
clinical trial conducted at the University
of Texas MD Anderson Cancer Center,
a formal meeting has been scheduled
with the United States Food and Drug
Administration (FDA) to discuss a
proposed Phase 3 clinical trial program.

For this Phase 3 program, the
patented allogeneic, or "off-the-shelf,"
Mesenchymal Precursor Cells (MPCs)
will be used under a United States FDA
Orphan Drug Designation to expand
haematopoietic stem and progenitor
cell numbers in patients with
haematologic malignancies.

Mesoblast's objective is to develop a
therapy that results in effective bone
marrow reconstitution without the
potentially life-threatening complication
of graft-versus-host disease which
occurs in as many as 60 percent of
patients who receive bone marrow
transplants from unrelated adult

In the first 25 patients transplanted
with MPC-expanded haematopoietic
progenitors from cord blood, 80
percent successfully achieved the key
composite endpoint at 100 days of
survival with sustained engraftment of
both neutrophils and platelets.  This is
significantly higher than the rate of 38
percent for this composite endpoint
achieved after transplantation with non-
expanded cord blood in the United
States registry of 300 patients
collected by the Center for
International Blood and Marrow
Transplant Research. To date, only
four patients (16 percent) receiving
expanded cord blood have developed
severe graft-versus-host disease.