HIV drug reduces graft-vs.-host disease in bone marrow transplant patients, Penn study shows

New approach redirects new immune cells from harming vital organs, without dangers of immunosuppression

2012-07-12

(Press-News.org) PHILADELPHIA -- An HIV drug that redirects immune cell traffic significantly reduces the incidence of a dangerous complication that often follows bone marrow transplants for blood cancer patients, according to research from the Perelman School of Medicine at the University of Pennsylvania that will be published today in the New England Journal of Medicine. The findings represent a new tactic for the prevention of graft-versus-host disease (GvHD), which afflicts up to 70 percent of transplant patients and is a leading cause of deaths associated with the treatment.

Allogeneic bone marrow transplantation – also known as stem cell transplantation – involve the transfusion of a matched donor's blood stem cells to rebuild the patient's bone marrow after treatment has eliminated both the defective blood cells associated with their cancer and their healthy blood cells.

"It appears that our new approach allows us to prevent some patients from developing GvHD by redirecting immune cells away from certain sensitive organs that they could harm," says lead author Ran Reshef, MD, an assistant professor in the division of Hematology-Oncology and a member of the Hematologic Malignancies Research Program at Penn's Abramson Cancer Center. "This is a novel way for us to try to decrease treatment-related complications among bone marrow transplant patients without also reducing their new immune system's ability to attack their cancer."

Typically, patients receive immunosuppressive drugs following their transplant to lower the risk of developing graft-versus-host disease (GvHD), which occurs when the newly transplanted immune cells attack healthy tissue they perceive as foreign. But since patients' own immune systems must be wiped out in order to receive their transplants, those drugs leave patients even more vulnerable to life-threatening infections and to a relapse of their cancer. The Penn team found that treatment with the HIV drug maraviroc dramatically reduced the incidence of GvHD in organs where it is most dangerous – the liver and gut -- without compromising any other function of the immune system.

The findings, which involved repurposing maraviroc -- approved for HIV treatment in 2007 -- could represent a breakthrough for prevention of GvHD. Reshef and his co-authors showed that the drug is safe in BMT patients who receive stem cells from a healthy donor, and that a brief course of the drug led to a 73 percent reduction in severe forms of GvHD in the first six months after transplant, compared with the incidence rate typically seen in similar patients who do not receive maraviroc.

"Just like in real estate, immune responses are all about location, location, location," Reshef says. "Cells of the immune system don't move around the body in a random way. There is a synchronized and well orchestrated process whereby cells express particular receptors on their surface that allow them to respond to small proteins called chemokines, which direct the immune cells to specific organs where they are needed -- or in the case of GvHD, to where they cause damage. We're using maraviroc, which was initially designed to prevent certain types of HIV from entering healthy cells in the body, as a traffic signal to direct the donor's immune cells away from those places in the body where they might cause GvHD."

Thirty-eight patients with blood cancers, including acute myeloid leukemia, myelodysplastic syndrome, lymphoma, myelofibrosis and others, were enrolled in the trial. All patients received the standard GvHD prevention drugs tacrolimus and methotrexate, plus a 33-day course of maraviroc that began two days before transplant. In the first 100 days after transplant, none of the patients treated with maraviroc developed GvHD in the gut or liver, which are the most severe forms of the illness. At six months, only six percent of patients treated with maraviroc had severe graft-versus-host disease, only three percent had it in their liver, and nine percent had it in their gut. Among similar patients who receive standard drugs without maraviroc, rates of severe GvHD six months after transplant are 22 percent, with liver and gut involvement seen in 15 and 27 percent of patients, respectively. At one year, the benefit of maraviroc appeared to be partially sustained, with a cumulative incidence of severe GvHD of only 15 percent, as opposed to 29 percent in patients who receive standard therapy.

Based on these data, the research team plans to try a longer treatment regimen with maraviroc in future studies, to see if they could prolong the protective effect.

The differential impact of maraviroc on the liver and gut indicates that the drug is working as expected, by limiting the movement of immune cells called T lymphocytes to specific organs in the body. Maraviroc works by blocking the CCR5 receptor on lymphocytes, preventing the cells from trafficking to certain organs. The researchers saw no effect on skin GvHD, so they theorize that the CCR5 receptor might be more important for recruiting lymphocytes into the liver and the gut than for the skin.

Maraviroc treatment did not appear to increase treatment-related toxicities in these patients, nor did it alter the relapse rate of their underlying disease or risk of infection, and it did not slow the amount of time it took for patients' new immune systems to engraft in their bodies.

### David Porter, MD, professor of Medicine and director of Blood and Marrow Transplantation in the Abramson Cancer Center, and Robert Vonderheide, MD, DPhil, associate professor of Medicine and Associate Director for Translational Research at the Abramson Cancer Center, are the senior authors of the study. Funding support for this investigator-initiated trial comes from the Abramson Cancer Center, the Leukemia and Lymphoma Society, the American Society of Hematology, the National Cancer Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health (K24-CA117879, P30-CA16520, and U01-HL069286), the American Society of Clinical Oncology, and Pfizer, the maker of maraviroc.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise. Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.

ELSE PRESS RELEASES FROM THIS DATE:

2 proteins offer a 'clearer' way to treat Huntington's disease

2012-07-12

In a paper published in the July 11 online issue of Science Translational Medicine, researchers at the University of California, San Diego School of Medicine have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). The findings explain a fundamental aspect of how HD wreaks havoc within cells and provides "clear, therapeutic opportunities," said principal investigator Albert R. La Spada, MD, PhD, professor of cellular and molecular medicine, ...

Weight loss resulting from a low-fat diet may help eliminate menopausal symptoms

2012-07-12

OAKLAND, Calif. July 11, 2012 – Weight loss that occurs in conjunction with a low-fat, high fruit and vegetable diet may help to reduce or eliminate hot flashes and night sweats associated with menopause, according to a Kaiser Permanente Division of Research study that appears in the current issue of Menopause. This Women's Health Initiative study of 17,473 women found that women on a diet low in fat and high in whole grains, fruit and vegetables, who had menopausal symptoms, who were not taking hormone replacement therapy, and who lost weight (10 or more pounds or 10 ...

Individual differences in altruism explained by brain region involved in empathy

2012-07-12

What can explain extreme differences in altruism among individuals, from Ebenezer Scrooge to Mother Teresa? It may all come down to variation in the size and activity of a brain region involved in appreciating others' perspectives, according to a study published by Cell Press in the July 12th issue of the journal Neuron. The findings also provide a neural explanation for why altruistic tendencies remain stable over time. "This is the first study to link both brain anatomy and brain activation to human altruism," says senior study author Ernst Fehr of the University of ...

Oral contraceptive use in girls and alcohol consumption in boys are associated with increased BP....

2012-07-12

Lifestyle behaviour in adolescents may adversely affect blood pressure and cardiovascular risk in adulthood, according to results from a large pregnancy follow-up study in Australia.(1) In particular, alcohol consumption among boys, use of the Pill among girls, and high salt intake and increasing body mass index (BMI) in both sexes were important factors linked to blood pressure levels in late adolescence. The substantial differences in blood pressure found in the study between those with a healthier or less favourable lifestyle "are likely to significantly affect their ...

Native American populations descend from 3 key migrations

2012-07-12

Scientists have found that Native American populations — from Canada to the southern tip of Chile — arose from at least three migrations, with the majority descended entirely from a single group of First American migrants that crossed over through Beringia, a land bridge between Asia and America that existed during the ice ages, more than 15,000 years ago. By studying variations in Native American DNA sequences, the international team found that while most of the Native American populations arose from the first migration, two subsequent migrations also made important genetic ...

Dark galaxies of the early Universe spotted for the first time

2012-07-12

Dark galaxies are small, gas-rich galaxies in the early Universe that are very inefficient at forming stars. They are predicted by theories of galaxy formation and are thought to be the building blocks of today's bright, star-filled galaxies. Astronomers think that they may have fed large galaxies with much of the gas that later formed into the stars that exist today. Because they are essentially devoid of stars, these dark galaxies don't emit much light, making them very hard to detect. For years astronomers have been trying to develop new techniques that could confirm ...

High-density lipoprotein still matters, look at the particles!

2012-07-12

Boston, MA—Until recently, it seemed well-established that high-density lipoprotein (HDL) is the "good cholesterol". However there are many unanswered questions on whether raising someone's HDL can prevent coronary heart disease, and on whether or not HDL still matters. A team of researchers at Brigham and Women's Hospital (BWH), the University of Pittsburgh Graduate School of Public Health (GSPH) and other institutions, have discovered that measuring HDL particles (HDL-P) as opposed to HDL cholesterol (HDL-C) is a much better indicator of coronary heart disease (CHD), ...

Smart materials get SMARTer

2012-07-12

Cambridge, Mass. – July 11, 2012 – Living organisms have developed sophisticated ways to maintain stability in a changing environment, withstanding fluctuations in temperature, pH, pressure, and the presence or absence of crucial molecules. The integration of similar features in artificial materials, however, has remained a challenge—until now. In the July 12 issue of Nature, a Harvard-led team of engineers presented a strategy for building self-thermoregulating nanomaterials that can, in principle, be tailored to maintain a set pH, pressure, or just about any other desired ...

Researchers 1 step closer to new kind of thermoelectric 'heat engine'

2012-07-12

COLUMBUS, Ohio - Researchers who are studying a new magnetic effect that converts heat to electricity have discovered how to amplify it a thousand times over - a first step in making the technology more practical. In the so-called spin Seebeck effect, the spin of electrons creates a current in magnetic materials, which is detected as a voltage in an adjacent metal. Ohio State University researchers have figured out how to create a similar effect in a non-magnetic semiconductor while producing more electrical power. They've named the amplified effect the "giant spin-Seebeck" ...

Anxiety linked to shortened telomeres, accelerated aging

2012-07-12

BOSTON, MA—Is anxiety related to premature aging? A new study by researchers at Brigham and Women's Hospital (BWH) shows that a common form of anxiety, known as phobic anxiety, was associated with shorter telomeres in middle-aged and older women. The study suggests that phobic anxiety is a possible risk factor for accelerated aging. The study will be electronically published on July 11, 2012 in PLoS ONE. Telomeres are DNA-protein complexes at the ends of chromosomes. They protect chromosomes from deteriorating and guard the genetic information at the ends of chromosomes ...