Precision Medicine Overcomes Radiation Resistance in Leukemia Treatment

Engineered protein improves survival rates in aggressive leukemia.

A newly designed engineered protein was able to overcome radiation resistance in leukemia treatment during a recent study.

Published in the journal EBioMedicine, the study examined the new precision medicine for the treatment of B-precursor acute lymphoblastic leukemia (ALL). Despite the use of intensive chemotherapy, some ALL patients experience a disease relapse, which carries a very poor long-term survival rate.

Current treatment standards for relapsed ALL patients includes intensive chemotherapy to achieve a second remission, which is typically followed by aggressive treatment that could involve total-body irradiation (TBI) and hematopoietic stem cell transplantation, the study noted. The radiation resistance of leukemia cells can dampen the success of these rigorous treatment regimens, however.

"Despite advances in available therapies, unmet and urgent needs remain in the fight against leukemia. We still have children with disease that our drugs can't help enough, and for patients who relapse, their chances of long-term survival are less than 20%. We've got to do better," lead researcher Fatih M. Uckun, MD, PhD, said in a press release. "Therefore, discovering a way to overcome the radiation resistance of ALL has been one of the most urgent unmet challenges in cancer therapy.”

The results of the study suggest that radiation resistance in aggressive leukemia can be overcome using the rationally-designed specific protein-based medicine, which enhances the efficacy of radiation therapy against the most aggressive and treatment-resistant forms of the disease.

"Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with the new precision medicine that was named CD19L-sTRAIL (CD19 Ligand-soluble TRAIL fusion protein)," Dr. Uckun said.

CD19L-sTRAIL was engineered as a fusion of the CD19 Ligand protein, which locates and binds to leukemia cells, with soluble TRAIL, a protein that increases radiation potency when attached to leukemia cell membranes, according to the study.

"Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL, and consistently killed aggressive leukemia cells taken directly from children with ALL -- not only in the test tube, but also in mice," Dr. Uckun said.

In mice where TBI did not improve survival with an otherwise lethal dose of leukemia cells drawn from human patients, the addition of just 1 to 3 doses of CD19L-sTRAIL to radiation therapy improved potency by 260%, which led to long-term leukemia-free survival without significant side effects.

"We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia," Dr. Uckun concluded.