Eliminating ‘Friendly Fire’ in BMT Patients

BMT Immunotherapy
Like an outpost soldier, the immune system is always on watch for strangers. The problem is, sometimes it can’t determine friend from foe—attacking healthy tissue instead of cancerous tumors.

Two researchers in Atlanta, Dr. Leslie Kean and Dr. Jacques Galipeau, are trying to correct this problem with novel approaches that have worked with live test subjects—and might work with humans. Both work in immunotherapy, a growing field of treatment options that use characteristics of the body’s immune system to fight a wide array of disease.

Kean, of the Aflac Cancer Center of Children’s Healthcare of Atlanta and Emory University, is focusing on stopping the effects of Graft-versus-host-disease, or GvHD, a common, but potentially deadly complication of bone marrow transplants used to treat primarily leukemia.

Rates of GvHD vary from between 30 to 40 percent among related donors and recipients to 60 to 80 percent between unrelated donors and recipients—with up to half of patients dying from this complication. The greater the mismatch between donor and recipient, the greater the risk of GvHD.

GvHD, which often attacks the liver, skin and GI tract, develops because the marrow or the stem cells contain blood cells from the donor, including T-cells—which then launch an attack on the transplant recipient’s tissues and organs—potentially unraveling all the curative effects of the transplant.

“Given the lack of success in preventing (GvHD) with current therapies, novel therapies to prevent this disease are desperately needed,” according to an initial grant application filed more than a decade ago with the National Cancer Institute.

Kean’s ground-breaking solution is to give the recipient “T-cell immunity” allowing them to take the donor marrow and cells but resist an assault of a host’s T-cell attack. It’s a difficult balance to obtain, the donor’s T-cells can actually be useful in “engraftment” and preventing a cancer relapse, especially in patients whose own T-cells have been depleted through other treatments. But if allowed to run rampant, the host’s T-cells turn on the very patient the transplant is supposed to help.

Kean has found, however, that she can tamp down the damage by inhibiting the donor’s T-cell function by using an antibody—or a group of antibodies, used together as a “co-stimulation blockade.”

Kean and her team have used two co stimulation blockade agents: Abatacept and a related compound called Belatcept.

Both of these work by binding to the protein in the T-cells that directs the attack on the recipients’ tissue. But the challenge has been to find the “sweet spot” where enough T cells are used to destroy sickness, but enough are also disabled so the recipient remains healthy.

“It would be huge success if the current 35 percent rate for GvHD for unrelated transplants could be reduced to 15 percent,” she said. Right now, with clinical trials under way, hopes are high that her treatment will not only be effective, but will be safe and tolerable in the pediatric population as well.

“It would be a great thing if we could reduce the damage,” she said. “GvHD can be devastating and deadly, and this might give doctors tools they simply don’t have right now.”

And if her treatment does as well as Kean hopes, it has not only applications for leukemia, but a host of other blood related illnesses that plague children—including sickle cell, aplastic anemia and inherited immune deficiencies.

Similarly, Dr. Jacques Galipeau with Emory University and the Winship Cancer Institute as a visiting professor in hematology and medical oncology, is working on pediatric research topics that include tumor immunology and cellular therapies for autoimmune disorders.

In his model, however, he takes “B cells”—the workhorses of the immune system—from a recipient’s own blood or marrow and manipulates and strengthens them. “We put them through a boot camp, so to speak,” he said.

Typically, the B cells produce antibodies against bacteria and viruses, but researchers have also found that their behavior can also tamp down the immune system—and could be extremely effective in fighting complications such as GvHD, or illnesses such as Crohn’s Disease, juvenile arthritis or multiple sclerosis.

The cells normally live in the bone marrow—but not at the strength Galipeau needs. Typically, they’re rare: 1 in 100,000. But he will grow up to a 100 billion of them and give them back to the patient. And because they’re from the patient, there’s very little chance of rejection.

Already, Galipeau led a multidisciplinary team of researchers in developing a treatment that put multiple sclerosis into remission in mice by suppressing the immune system. The work was published in the September 2009 issue of Nature Medicine.

The treatment, named GIFT15, puts MS into remission by fusing together two proteins (GSM-CSF and Interleukin-15) which suppresses the immune system.

"You know those mythical animals that have the head of an eagle and the body of a lion? They're called chimeras. In a lyrical sense, that's what we've created," Galipeau said in a 2009 interview. "GIFT15 is a new protein hormone composed of two distinct proteins, and when they're stuck together they lead to a completely unexpected biological effect."

The first human clinical study could happen soon, Galipeau said, depending on funding. Already, researchers have taken the cells from eight children with Crohn’s Disease to prepare for testing.

And both researchers are encouraged by early results. Kean, who is wary of hyperbole, nonetheless is excited about the progress she has witnessed in her studies through the years.

When asked about what her own children think of her career, she’s quiet for a moment and then smiles. “They know mom is trying to do something important,” Kean said. “That she is trying to make a difference.”