Scientists gaining on graft-versus-host disease

May 2, 2019 | by Abe Rosenberg

Zeng-Defu Defu Zeng
This story is part of a series that explores the success of City of Hope’s bone marrow transplant program, which recently performed its 15,000th transplant.
 
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Whether it's a stubborn case of leukemia, lymphoma, multiple myeloma or even an obscure disorder like blastic plasmacytoid dendritic cell neoplasm, frequently only one treatment option offers hope for a cure: a stem cell transplant — rebuilding a patient's blood production system by swapping out the body's “bad” bone marrow (where blood cells are produced) for “good” cells provided by a donor.
 
Since beginning its bone marrow transplant (BMT) program in 1976, City of Hope doctors have performed more than 15,000 bone marrow and stem cell transplants, achieving remarkable success and ever-higher blood cancer survival rates.
 
Yet every time a transplant is performed, the built-in danger of graft-versus-host disease (GVHD) lurks. The donated cells may turn around and attack healthy tissues in the recipient's body, damaging the skin, eyes, lungs, liver and digestive tract.
 
Ironically, GVHD is caused by the very element that helps a transplant succeed in the first place.

Friend and Foe

Along with stem cells, doctors also implant donor immune cells — or T cells — into the patient. This is necessary in order to wipe out any lingering cancer cells not destroyed by the pretransplant regimen of total body irradiation or high-dose chemotherapy. Without those T cells, the transplant won't work — even if the stem cells do take root, the cancer may come back.
 
“Cancer cells are like cockroaches. It's hard to get them all,” said Department of Hematology & Hematopoietic Cell Transplantation Professor Defu Zeng. “You need the T cells to eliminate residual cancer cells.”
 
But it's those very T cells — programmed by nature to destroy foreign invaders — that do the damage of GVHD, by perceiving their new surroundings as “foreign” ... and attacking.
 
The traditional way to prevent GVHD used drugs to suppress the patient's entire immune system, but this approach also reduces the transplant's cancer-fighting properties. The goal, then, is to somehow “thread the needle,” maintaining as much anti-cancer power as possible without endangering healthy tissue.
 
Zeng has focused on that goal for much of his 15-year tenure at City of Hope. He and his lab are working on several possibilities.

Diversion

Organs most susceptible to GVHD — the gut, skin, lungs and liver — can't be harmed if donor T cells never reach them. But those “target” organs send out signals, or chemokines, that attract T cells, especially the CD4+ and CD8+ variety that have specific homing and chemokine receptors.
 
So Zeng uses an antibody called “anti-CD3” to “precondition” recipients before the transplant. Anti-CD3 prevents GVHD target tissues from releasing those signals. The result is that the donor CD4+ and CD8+ cells have no motivation to migrate where they shouldn't, but they'll still travel to the bone marrow, lymph nodes and spleen, where they can do their cancer-fighting work.
 
“We don't suppress the T cells,” he explains. “We educate them. We modulate them.”

Fine-Tuning

Another option is to allow donor T cells to roam anywhere they please, but to strengthen the GVHD target tissues’ ability to fight them off.
 
“We want to make GVHD target tissues resistant to damage and also make those donor T cells more susceptible to protective mechanisms,” said Zeng.
 
One way this is done is by depleting the donor CD4+ T cells but not the CD8+ cells. CD4+ cells carry the signaling molecule IL-2, which can “short circuit” the normal controls that prevent T cells from attacking healthy organs. Depleting CD4+ T cells leaves that protection in place, effectively preventing GVHD, while the CD8+ cells are free to destroy cancer cells where they're typically found, in the lymphoid system.
 
An alternate strategy would be to neutralize the recipient's IL-2 shortly after the transplant.
 
And yet another possibility would be to deplete the donor's STAT3 protein. STAT3 is the so-called “master switch” that activates the body's immune response. Depleting STAT3 may also prevent T cells from interacting with B cells, which has been shown to increase inflammation and lead to the more chronic form of GVHD.
 
“It's all about fine-tuning,” Zeng said.
 
And it takes time. Zeng estimates the first patient-ready treatments derived from his strategies are at least three to five years away. But he's optimistic. And excited.
 
“The more I do, the more I'm fascinated,” he said. “And I feel more and more confident that we will find a way to minimize GVHD and maximize the transplant's benefit to the patient.”
 
Everything, said Zeng, is about the patient. That's certainly not an unusual sentiment to hear on the City of Hope campus, where even researchers who never come in contact with patients nevertheless understand the urgency of their mission.
 
“I've treated patients. When we talk about translational research around here, I know what that's going to look like.”
 
And he knows the look he's striving for.
 
“We're providing hope,” he says. “My goal is to make the patient smile.”
 
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