Chuck Bednar for redOrbit.com – Your Universe Online
A new protein-based treatment could help treat acute lymphoblastic leukemia (ALL) patients whose cancer cells have developed resistance to contemporary chemotherapy, according to new research published online Monday in the Journal of Clinical Investigation.
ALL is the most common form of childhood cancer, and researchers at Children’s Hospital Los Angeles hope that the new therapy method they designed and developed will be effective against the leukemia cells, while increasing the potency of standard treatment options as well.
According to the study authors, their work demonstrated the efficacy and safety of their fusion protein in mouse models of aggressive human leukemia, which were created using cancer cells taken directly from patients who have ALL.
“Despite advances in available therapies, unmet and urgent needs remain in the fight against leukemia,” principal investigator Dr. Fatih M. Uckun of the of the Children’s Center for Cancer and Blood Diseases at CHLA and the Norris Comprehensive Cancer Center of the University of Southern California (USC), said in a statement.
“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,” he added.
Their research focused on a protein known as TNF-related apoptosis-inducing ligand (TRAIL), which functions as a ligand in order to induce cell death or apoptosis. TRAIL is produced by a person’s immune system cells, and has the potential to cause apoptosis in tumor cells by binding to a pair of so-called “death receptors” – TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” Dr. Uckun explained. “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.”
However, he and his colleagues have discovered a previously unknown protein that serves as a natural ligand of human CD19, which is expressed by nearly all ALL cells. They hypothesized that this protein, which is known as CD19-Ligand, could be fused to the part of TRAIL known to kill cancer cells (sTRAIL) to create a powerful weapon against leukemia.
Unlike chemotherapy drugs, which destroy all types of cells in the body, this bioengineered substance would seek out only leukemia drugs carrying CD19. It would then bind to them using CD19 as a “docking site” and destroy them, leaving healthy cells unharmed in the process.
During their experiments, Dr. Uckun’s team was able to assemble the two proteins in one fusion protein which they dubbed CD19L-sTRAIL. They also demonstrated that their efforts converted sTRAIL into a far more potent “membrane-anchored” form capable of triggering apoptosis in even the most aggressive and therapy-resistant type of human leukemia cells.
“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,” Dr. Uckun said.
It proved effective in both test tubes and in mice, he added. Administering as little as two doses of CD19L-sTRAIL significantly improved the survival rates of rodents infected with a normally fatal dose of ALL cells, and did so without side effects. Furthermore, it was found to be more potent than standard chemotherapy combinations and radiation therapy.
“The biggest challenge is to cure patients who experience a recurrence of their cancer, despite intensive chemotherapy,” Dr. Uckun noted. “We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia.”
—–
Follow redOrbit on Twitter, Facebook, Google+, Instagram and Pinterest.
Comments