Stanford Claims Progress Against GvHD

New Marrow Transplant Method Developed At Stanford May Eliminate
Fatal Side Effects
12/6/2004

Source: Stanford University

Bone marrow transplantation can cure lymphomas and leukemia, but in
about half of the cases transplanted immune cells wind up attacking
the patient's body, as well as the cancer.

In response to this problem, researchers at the Stanford University
School of Medicine have developed a technique that can virtually
eliminate this life-threatening complication, known as graft-versus-
host disease, without compromising the transplanted cells'
effectiveness against cancer.

The therapy entails adjusting the patient's level of a specific type
of immune cell, the regulatory T cells, before the transplant is
done. The method was first developed in mice by Samuel Strober, MD,
professor of medicine (immunology and rheumatology), who has been
studying these types of cells for more than 25 years. Robert Lowsky,
MD, assistant professor of medicine (bone marrow transplantation),
has adapted this strategy for humans along with Strober, and will
present the results of tests Dec. 6 at the annual American Society of
Hematology meeting in San Diego.

In two clinical trials funded by the National Institutes of Health,
Lowsky, Strober and other colleagues found that only one of the 37
patients who received the treatment developed graft-versus-host
disease. "You would have expected something in the order of 30 to 60
percent incidence of severe graft-versus-host disease in these
patients, according to conventional methods," said Strober.

Studies of the new method found there was no increase in the rate of
infections in the treated patients. The studies also found that the
majority of patients who were in partial remission went into complete
remission, and those who were in complete remission didn't relapse.

"It looks like there is a potent anti-tumor effect from our method
despite the incidence of graft-versus-host disease being dramatically
lowered," said Lowsky.

Also at the conference, Strober will conduct a session in which he
reviews the checkered history of regulatory T cells. For years
immunologists were polarized into groups who believed in the cells,
once known as suppressor T cells, and those who doubted their
existence. But with the development of more advanced techniques for
distinguishing between the different types of immune system cells,
the existence of the regulatory T cells has been confirmed. The
latest research suggests that the regulatory T cells act as the
immune system's peacekeepers, signaling to other T cells when to hold
off from attacking an intruder.

"The news going into this meeting is that the field of regulatory T
cells has not only come out of the clouded period that it was in, but
is now being accepted and adapted into clinical trials as a
conceptual framework for achieving certain desirable outcomes, for
example in the area of bone marrow transplantation," said Strober.

Always a proponent of the existence of regulatory T cells, Strober
worked out over the years a strategy using irradiation and antibodies
to increase the relative amount of regulatory T cells in the immune
tissues of host mice from about 1 percent of the total T cells to
more than 90 percent. By increasing the relative amount of these
cells, he found that he could retain the desired effect of killing
cancerous cells following bone marrow transplantation, but eliminate
the attack on host tissues. "It allows you to throw out the one
effect but not the other," he said.

Lowsky said he and Strober have now taken Strober's animal model and
translated it to the clinical setting for people. Although they have
not yet gathered conclusive evidence that this cellular process
worked the same in humans as it did in mice-that would require doing
direct examinations of cells from patients' spleens or lymph nodes-
Lowsky said their evaluations of the blood and marrow samples suggest
that is the case.

Now that the method is proving to be a viable therapy for humans, the
team will be testing it with other cancer centers.

Others involved in the clinical trial are Robert Negrin, MD,
professor of medicine; Yinping Liu, MD, a staff research associate
and Judith Shizuru, MD, PhD, associate professor of medicine, all in
the bone marrow transplantation division, and Tsuyoshi Takahashi, MD,
a research fellow in Strober's lab.