Scientists at the Children’s Hospital Los Angles (CHLA) have developed a new and much needed treatment to combat drug resistance in the most common childhood cancer, acute lymphoblastic leukemia (ALL). The researchers believe that their new protein-based therapy will not only be effective at treating resistant ALL, but may also increase the efficacy for the current standard of care, radiation and chemotherapy.
ALL accounts for roughly 25% of the diagnosed cancer cases among children under the age of 15. Until recently, ALL had a mortality rate of nearly 80%, but those numbers have been reversed with the design of new drugs and improvements in patient care. While almost 80% of current childhood ALL cases achieve long-term survival, researchers have been searching for ways to treat patients whose disease is less responsive to existing drug regimens and don’t fall into the long-term survival category.
“That’s great news, unless your child is one of 20 percent,” says Faith M. Uckun, M.D., Ph.D., of the Children’s Center for Cancer and Blood Disease at CHLA and lead author of the study. “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.”
Dr. Uckun and her team discovered a protein, CD19L, which is expressed on almost all cells and is a ligand to the B-cell antigen CD19. They then genetically fused CD19L to a portion of another protein, TNF-related apoptosis inducing ligand (TRAIL), which is known to be involved in the cells apoptotic or programmed cell death pathways.
“TRAIL is a naturally occurring part of the body's immune system that kills cancer cells without toxicity to normal cells. However, earlier clinical trials using TRAIL as a potential anti-cancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to 'decoy' receptors,” explained Dr. Uckun.
The fusion protein that the CHLA team generated, CD19L-sTRAIL, was able to demonstrate specific triggering of apoptosis in the most aggressive drug-resistant from of human leukemia cells. Unlike standard chemotherapy, which tends to have broad specificity toward cancer, as well as other off- target cells, CD19L-sTRAIL has the ability to seek out and destroy only leukemia cells carrying the CD19 ligand.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL, and consistently killed more than 99 percent of aggressive leukemia cells taken directly from children with ALL—not only in the test tube, but also in mice,” stated Dr. Uckun.
The investigators are hopeful that this study will open the door to new methodologies and treatment options for patients with resistant and recurrent leukemia.
The results from CHLA team’s analysis are published in the Journal of Clinical Investigation in an article entitled “Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia.”