A recent study published in the journal EBioMedicine has determined a way to overcome radiation resistance in leukemia using an engineered protein as a new precision medicine to fight leukemia. The team was led by Fatih M. Uckun from The Saban Research Institute of Children’s Hospital Los Angeles and also Professor at the University of Southern California Keck School of Medicine.
The most frequent type of cancer in children and adolescents is B-precursor acute lymphoblastic leukemia (ALL). After intensive sessions of chemotherapy, some patients have relapses and cancer recurrence, reducing their long-term survival prospects.
The standard strategy to treat relapsed patients involves intensive chemotherapy. As such, a second remission is achieved after very intensive treatment that could include total-body irradiation (TBI), “supralethal” chemotherapy and hematopoietic stem cell transplantation. Nevertheless, leukemia cells’ radiation resistance obstructs the success of these therapeutic approaches and ultimately results in poor survival.
“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 percent. We’ve got to do better. Therefore, discovering a way to overcome the radiation resistance of ALL has been one of the most urgent unmet challenges in cancer therapy,” noted Dr. Uckun in a press release.
Uckun and his research team found the first proof-of-principle that radiation resistance of aggressive leukemia can actually be overcome through this rationally-designed specific protein-based medicine that augments the efficacy of radiation therapy.
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“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 (short for CD19 Ligand – soluble TRAIL fusion protein),” said Uckun. CD19L-sTRAIL results from genetic engineering of the CD19 Ligand protein fused with soluble TRAIL, a ligand that can increase the power of radiation when anchored to leukemia cells’ membranes.
“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,” commented the researcher. When overall body irradiation failed to increase mice survival challenged with lethal doses of human leukemia cells (collected directly from patients), simply adding 1 to 3 doses of this novel medicine to the radiation regimen increased its efficiency by 260 percent 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,” concluded Dr. Uckun.
