Researchers at the University of Michigan's Comprehensive Cancer Center 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.
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."