You may have heard of successful cancer immunotherapies known as immune checkpoint inhibitors, which work by releasing a molecular “brake” that restrains the immune system. Duke researchers have now designed an antibody that not only releases an immune system brake but also directs immune cells to their targets.
In study results reported in Science Translational Medicine, the researchers, led by Mihai Azoitei, PhD, Barton F. Haynes MD, and Joyce Hwang, MD, PhD, demonstrated that the engineered antibody can target cancer cells and virus-infected cells that use a molecule called HLA-E to hide from immune attack.
HLA-E is normally found on healthy cells, where it helps signal that they should be left alone. But cancer cells and cells infected with certain viruses can increase HLA-E levels to shield themselves from immune defenses. The Duke team developed antibodies that bind tightly to HLA-E, stripping away that protection and marking the diseased cells for destruction.
In lab studies, the approach enhanced the activity of two arms of the immune system (natural killer cells and CD8+ T cells) to destroy both cells infected by HIV and cancer cell lines that overexpressed HLA-E. The antibodies also helped natural killer cells clear human cell line tumors in mice.
"HLA-E is an example of a shared mechanism of immune evasion by viruses and tumors,” said Hwang, a Duke Human Vaccine Institute postdoctoral fellow and recent clinical fellow in hematology-oncology. “This interdisciplinary work, a particular strength at Duke, is teaching us key points of leverage toward new immune therapies.”
Next, the team will study this approach in models that better resemble disease caused by both viruses and cancerous cells. “We want to see if targeting HLA-E complexes can work as a broad therapeutic approach to clear hidden stores of pathogenic cells across conditions,” Azoitei said.
In addition, they will study the safety of the approach carefully. “Since HLA-E is also present on healthy tissue, we want to be sure we can target diseased cells without affecting normal ones,” he said.
Other Duke authors: Marina Tuyishime, Daniel J. Marston, Daniel Wrapp, Dapeng Li, McKenzie Frazier, Nicholas P. Levering, Richard Scearce, Brianna Rhodes, Caitlin Harris, A. Brenda Kapingidza, Jacob Gater, Guido Ferrari.
Funding: The National Institutes of Health (NIAID), the Bill and Melinda Gates Foundation, the Duke Cancer Institute Cancer Center Support Grant.