University of Michigan researchers have discovered the secret weapon behind the most powerful form of cancer immunotherapy known to medicine. Scientists call it the graft-versus-leukemia effect, and it occurs when new immune cells from donated bone marrow, called the graft, attack malignant cells in the patient and destroy them. This intense immune reaction between donor and host cells, which follows a bone marrow transplant from a healthy donor, has saved the lives of thousands of patients with leukemia, lymphoma and other types of blood and immune system cancers.
Scientists call it the graft-versus-leukemia effect, and it occurs when new immune cells from donated bone marrow, called the graft, attack malignant cells in the patient and destroy them. This intense immune reaction between donor and host cells, which follows a bone marrow transplant from a healthy donor, has saved the lives of thousands of patients with leukemia, lymphoma and other types of blood and immune system cancers.
In a study to be published Oct. 16 in the advanced online edition of Nature Medicine, U-M scientists describe how antigen presenting cells are crucial to graft-versus-leukemia’s cancer-killing effect.
The discovery is significant, because it could help make cellular immunotherapy safer, more effective and an option for more cancer patients — especially those for whom a donor is unavailable or those who cannot tolerate the procedure’s side-effects.
"We already knew that donor T cells were important for an effective GVL response, but now we know there’s another cell — the antigen presenting cell or APC — which plays a critical role in the process," says James L.M. Ferrara, M.D., who directs the U-M Cancer Center’s Blood and Marrow Transplant Program.
Antigen presenting cells are rare immune system cells, which look something like a starfish. Their job is to digest proteins called antigens from foreign cells or pathogens and present them to T cells. This alerts the immune system to prepare to fight the invader. When APCs present cancer cell proteins to T cells, the T cells are primed to attack the cancer.
"We found that without functional APCs to process and present antigens to T cells, there is no graft-versus-leukemia response, and the cancer is likely to return," says Pavan R. Reddy, M.D., an assistant professor of internal medicine in the University of Michigan Medical School, who led the research study.
According to Reddy, the research results suggest that manipulating the number and activity of APCs could improve the GVL response, while reducing the risk of a common post-transplant complication called graft-versus-host disease, or GVHD.
"GVHD occurs when the donor’s immune cells attack the patient’s skin, liver and gastrointestinal tract," Reddy explains. "It triggers a massive inflammatory reaction that can kill the patient, especially if he or she is older or has other medical problems."
In an effort to eliminate GVHD, other researchers have suggested removing APCs from transplanted donor cells, according to Ferrara. "We know that APCs are involved in graft-versus-host disease, so people say let’s take out the APCs and then we will get the anti-cancer effect without the risk of GVHD," he explains. "This paper says, no, you can’t do that.
"There’s a tight link between the graft-versus-leukemia effect and graft-versus-host disease," Ferrara says. "Few patients get the beneficial effects of GVL without some degree of the toxic side effects of GVHD. But if we can find ways to reduce GVHD’s toxic effects, immunotherapy could become a viable option for many more cancer patients."
To study what happens during the graft-versus-leukemia effect, Reddy and his U-M colleagues used high doses of radiation to destroy the blood and immune systems of genetically different laboratory mice. After reconstituting each animal’s immune system, using either functional or non-functional APCs, the mice were inoculated with cancer cells and given a bone marrow transplant that could cure the cancer. The scientists then determined which mice died from acute graft-versus-host disease, which mice died from cancer and which mice generated a GVL response to destroy the cancer cells.
"The donor and host mice were paired in ways to make their antigen-presenting cells dysfunctional, either because they were of the same tissue type as the donor, or because they had a mutation that prevented them from displaying tumor antigens to T cells," Reddy explains. "Essentially we created animals where the tumor was the same, the antigens were the same, donor T cells were the same, but the APC was dysfunctional. Without a functioning APC, there was no graft-versus-leukemia effect."
Other researchers have suggested that tumor cells can present antigens to T cells directly to stimulate an immune response against cancer, but results from the U-M study indicate the response is too weak to be effective.
"APCs shred proteins, or antigens, from cancer cells and display those shredded proteins on their surface," Ferrara says. "Cancer cells have the same proteins, but haven’t gone through the APC’s shredding process. It’s as if APCs are master chefs who prepare the antigens in a way to make them especially delicious to T cells. So instead of taking just one bite, they go back for seconds or thirds."
In future research, U-M scientists will explore how to manipulate APC function in ways that will preserve their vital role in stimulating an immune response against cancer, while controlling the intensity of graft-versus-host disease. Reddy and Ferrara have studied drugs called HDAC inhibitors and found that they modulate APC function in mice. They hope to design an initial study of these drugs in post-transplant leukemia patients within a year.
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The research was funded by the National Cancer Institute. Collaborators included Yoshinobu Maeda, M.D., a former U-M research fellow; Oleg I. Krijanovski, M.D., a research fellow in internal medicine; Chen Liu, M.D., a pathologist at the University of Florida College of Medicine; and Robert Korngold, M.D., Ph.D., an immunologist and scientific director of the Hackensack University Cancer Center.
