While immune checkpoint inhibitors that target the PD-1 molecule on T-cells have proven to be effective with many cancers, these immunotherapies have not worked for acute myeloid leukemia (AML), but new research has identified a “cousin” molecule as a potential therapeutic target for AML.
Researchers have uncovered several characteristics of this “cousin” molecule called the PD-1H or VISTA that is also present in T cells and has a very similar structure. However, it functions differently. The researchers found that overexpression of VISTA promoted the growth of AML cells, mainly by evading T-Cell immune responses. In mouse models, they discovered that the ablation of VISTA molecules on T cells by either antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. Notably the combination of this VISTA blockade with existing anti-PD-1 immunotherapy conferred a synergistic antileukemia effect.
The findings were published in The Journal of Clinical Investigation.
“I hope VISTA blockade can help relapsed/refractory AML patients,” said lead and corresponding author, Tae Kon Kim, MD, PhD, assistant professor of Medicine and of Pathology, Microbiology, and Immunology at Vanderbilt University Medical Center.
More than 11,400 people in the United States die from AML each year, and new therapeutics are needed.
The mainstay treatment for AML is a therapy developed in the 1970s — the combination of anthracycline and cytarabine.
The researchers analyzed the Cancer Genome Atlas database, studied bone marrow core biopsies from AML patients, performed mouse model studies, initiated cell-line inquiries and other experiments during their investigation to prove that the PD-1H or VISTA molecule mediates immune system evasion in AML. They also revealed immune evasion occurs because VISTA suppresses infiltrating T cells in the leukemia microenvironment.
The researchers concluded that data from the study “strongly suggest that PD-IH is an important immune-suppressive molecule in AML that can be targeted” in AML patients.
Other Vanderbilt authors on the study include Qianni Hu, PhD, Carly Fielder, Kwang Woon Kim, PhD, Emily Mason, MD, PhD, and R. Skipper Plowman, MD.