Working together for children with cancer

February 26, 2010
Clinical trial will seek to calm down sickle-cell disease

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David Nathan, MD, was attending a cancer immunology conference where he heard about a potential drug treatment for cancer that would inhibit adenosine receptors, preventing immune cells that attack the cancer from being shut down. Nathan wasn't sure that such an approach would work in cancer, but a bell went off in his head, and he wondered whether adenosine or a drug like it might provide a key to another disorder – sickle-cell disease.

Nathan, Children's Physician-in-Chief from 1985-1995 and President Emeritus of the Dana-Farber Cancer Institute, is one of the world's top sickle-cell experts. In the 1980s, he and Orah Platt, MD, Chief of Laboratory Medicine at Children's, led the research introducing the only currently approved sickle-cell drug, hydroxyurea. And now, at the age of 80, he's leading a multicenter clinical trial of an adenosine-like drug known as Lexiscan for sickle-cell disease, aided by a two-year stimulus grant from the National Institutes of Health. The trial is hoped to begin recruiting by spring.

In sickle-cell disease, the body's small blood vessels become clogged with misshapen or "sickled" red blood cells, causing pain and eventually organ damage. However, a decade ago, Platt proposed that inflammation caused by white cells is a major problem in sickle-cell disease. "Most of us had a more mechanical view – that cells simply sickle and block blood vessels," says Nathan. "Platt's paper made us think more broadly about the problem."

It's now known that vessel blockage, which deprives tissues of oxygen, sparks an inflammatory response that greatly exacerbates patients' pain crises. It also exacerbates cell sickling, leading to more blockage – a devastating vicious cycle.

But it turns out inflammation has a natural brake: adenosine. When inflammation damages cells, they release their DNA, one component of which is adenosine. The adenosine then locks onto special adenosine A2A receptors on inflammatory cells, markedly reducing their activity.

"That's why you don't get continuous inflammation – tissue death causes the inflammation to go away," says Nathan. "For that reason, I thought maybe we could use an adenosine analogue to shut down this inflammatory response, and break the vicious cycle of sickle-cell crises."

After the conference presentation, Nathan discussed his idea with the conference's organizer, a world expert on adenosine receptors. He thought Nathan's idea sounded reasonable. "I then went to the web and just typed in ‘sickle cell' and ‘adenosine' to see if anyone else was thinking about it," Nathan says.

Very little came up, but there was one researcher, Joel Linden, PhD, of the La Jolla Institute of Allergy and Immunology, who was studying adenosine in mouse models of sickle cell disease. He'd found that activation of adenosine A2A receptors inhibited inflammation and tissue injury. He'd also zeroed in on the specific white blood cells causing most of the inflammatory havoc, known as iNKT cells or invariant natural killer T-cells.

iNKT cells normally constitute only 1 percent of all white blood cells. However, working with Joshua Field, MD, a young hematologist at Washington University in St. Louis who was providing patient blood samples, Linden had found that patients with sickle-cell disease have a 10-fold increase in these cells. And the cells, he showed, sport an abundance of adenosineA2 receptors on their surface.

What's more, a drug stimulating the adenosine A2 receptor was already available: Lexiscan. "We started talking, and said, ‘gee we should do a clinical trial,'" says Nathan.

In fall 2009, Nathan, Linden and other collaborators won a two-year NIH stimulus grant of $1.2 million to launch a Phase I trial in adults, and eventually children, with sickle-cell disease. Lexiscan (Astellas Pharma US) is currenty used in adults with coronary disease, given in brief, high doses during coronary stress testing. The new trial will test smaller doses of adenosine, administered for longer periods.

The trial will begin in adults with sickle-cell disease but no painful crises, giving different test doses of Lexiscan for periods of 12 and 24 hours to ensure that it doesn't cause toxicity. The team will then move quickly to test Lexiscan in adults with pain crises, and, in the second year, in children age 10 and older.

Ultimately, if these tests go well and the drug proves safe, they hope to test Lexiscan in sickle-cell patients with acute chest syndrome, or pulmonary crisis. "Pulmonary crisis is a very serious complication and may be fatal, because patients are unable to breathe," says Nathan. "We want to see if the drug will abort pulmonary crisis. We do know that it works very well in sickle-cell mice with pulmonary disease."

Nathan would also like to test Lexiscan in children younger than 10, but more toxicity work would first need to be done in animals. He hopes that if the early data are good, the drug manufacturer will support these studies. Meanwhile, studies in mice will test other drugs that might serve as alternatives to Lexiscan.

Matthew Heeney, MD, clinical director of the Sickle Cell Program at Children's, will be heading up the pediatric portion of the trial; adults will be seen at Brigham and Women's Hospital and Washington University and studied by Maureen Okam, MD, and Joshua Field, MD.

"We need to get plenty of patients in here fast," says Nathan. "If we can make all our milestones in two years, we will be invited to submit a renewal application for five years. We need to work at a fast pace – we've got to show whether this works."

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