Targeting exhausted immune cells may change the prognosis for patients with acute myeloid leukemia (AML) relapse after a stem cell transplant, according to a study recently published in Blood Cancer Journal (2015; doi:10.1038/bcj.2015.58). There is currently no effective treatment for this stage of leukemia, and patients have only a 5% chance of survival over 5 years.
AML is a fast-moving cancer of the blood and bone marrow. In patients with AML, the bone marrow produces abnormal white or red blood cells or platelets. Powerful rounds of chemotherapy can damage bone marrow, so many patients are given an infusion of blood-forming stem cells from a donor to restore it. These donor cells also help fight off any remaining leukemia cells, a phenomenon known as the graft-versus-leukemia (GVL) effect.
However, in some transplant patients, GVL fails and the cancer returns. These patients often cannot tolerate more chemotherapy, and they typically have less than 1 year to live.
After seeing many of her patients succumb to this, Hong Zheng, MD, PhD, assistant professor of medicine at Penn State College of Medicine in Hershey, Pennsylvania, decided to investigate why some patients relapsed while others did not. Comparing the blood of patients who relapsed to patients who did not led her to exhausted T cells.
T cells are a major player in the GVL effect. They send out cytokines, killer compounds that can directly or indirectly eradicate leukemia cells. But over time, fighting off invaders can tire out T cells, causing T cell exhaustion.
Zheng’s team found that relapse patients had significantly elevated levels of PD-1hiTIM-3+ cells, which are markers of T cell exhaustion. Their T cells also produced fewer cytokines, bolstering the idea that these immune-system soldiers were not functioning up to par.
These results could lead to new treatments sooner rather than later. There is currently a PD-1 antibody on the market that blocks T cell exhaustion in patients with solid tumors, such as lung cancer and melanoma. Zheng is planning a clinical trial to see if it could work for post stem cell transplant AML relapse patients as well.
She also believes the PD-1hiTIM-3+ cells could be used to diagnose relapses earlier than is currently possible. Catching relapses sooner opens the door to treatments, such as an infusion of donor T cells, which alone do not work once leukemia cells take over.
“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”
Zheng is currently investigating the trigger for T cell exhaustion in AML stem cell transplant recipients.
“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”