In a study with mice and cells taken from human patients with B-cell precursor acute lymphoblastic leukemia (BPL), a combined molecule involving the CD19 receptor and a protein called sTRAIL, showed potent anti-leukemic activity. The “fusion protein” created was far more potent than sTRAIL alone.
The sTRAIL protein induces cell death in certain cells, and preclinical and early clinical studies have shown a favorable toxicity profile, according to researchers led by Fatih M. Uckun, MD, PhD, of Children’s Hospital Los Angeles. There are many impediments to using sTRAIL alone as a therapeutic agent, however, including other receptors that compete for binding to the protein, as well as a short half-life in circulation. “It has been proposed that many of these limitations of sTRAIL can be overcome by genetically fusing it to a tumor-specific ligand or antibody,” they wrote.
In a study published on January 26 in the Journal of Clinical Investigation, Uckun’s group reported the fusion of a natural ligand of the human CD19 receptor (CD19L) to sTRAIL. If effective, this fusion protein would destroy only leukemic cells carrying CD19 as a docking site.
The researchers tested CD19L-sTRAIL in primary cells from 34 BPL patients. They found that the fusion protein caused 84% apoptosis, or cell death, compared to only 45% with 2 Gy ionizing radiation. Upping the concentration of the protein achieved even better results.
“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,” Uckun said in a press release.
A further study in which cells from five BPL patients were used to induce overt leukemias in mice also showed promise. Only two of 24 mice injected with the fusion protein developed leukemia; meanwhile, 28 of 28 mice injected with cells treated with either sTRAIL alone or CD19L alone developed leukemia (P < .0001). CD19L-sTRAIL was also found to be very well tolerated in the mice, without any evidence of acute or severe toxicity.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Uckun concluded.