In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to 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,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL 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% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“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 said.
