Histone deacetylase inhibitors enhance immunotherapy in lung cancer models, say Moffitt researchers
TAMPA, Fla. (March 31, 2016) – Several new immunotherapeutic antibodies that inhibit checkpoint receptors on T cells to restimulate the immune system to target tumors have been approved to treat advanced stage lung cancer and melanoma; however, only 20 percent of lung cancer patients show a response to these agents. Moffitt Cancer Center researchers have identified a class of drugs that improve the activity of immunotherapeutic antibodies by stimulating the movement of T cells into a tumor and enhancing their activity.
Tumors avoid detection by the immune system by increasing levels of immune-suppressive molecules, such as PD-L1. Antibodies that inhibit PD-1 and PD-L1 interaction can reactivate the immune system to target cancer cells.
Clinical studies have shown that not all patients respond to PD-1-targeted antibodies. Low levels of a type of immune cell called a T cell within a tumor are associated with a poor response to agents that target PD-1. Moffitt researchers hypothesized that small molecule drugs that could stimulate the movement of T cells into tumors could enhance the activity of PD-1-targeting drugs.
The researchers analyzed a panel of 97 FDA-approved agents for their ability to increase expression of chemical messengers called chemokines that stimulate T cell tumor infiltration and activity. They discovered that only one class of drugs called histone deacetylase (HDAC) inhibitors was capable of inducing T cell chemokine expression in vitro.
The team further demonstrated that the HDAC inhibitor romidepsin significantly decreases lung tumor growth in mice. They showed that romidepsin's anti-tumor effects are due to its ability to induce chemokines and T cell infiltration into tumors.
These observations suggest that HDAC inhibitors, including romidepsin, could work in conjunction with other immune-stimulating agents to enhance an immune response against tumors. The researchers confirmed this by showing that romidepsin combined with an antibody that targets PD-1 results in greater anti-tumor activity than either agent alone and increases the levels of T cells within the tumor and their activity.
Several HDAC inhibitors, including romidepsin, have been approved to treat hematologic malignancies; however, their single-agent activity in solid tumors, such as lung cancer, has not been as great.
"These results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment," said Amer Beg, Ph.D., senior member of the Immunology Program at Moffitt.
A clinical trial to test combination therapy of an HDAC inhibitor and a PD-1 inhibitor in stage IV non-small cell lung cancer has been initiated at Moffitt and is currently recruiting participants.
The study was published online March 10 ahead of print publication in the journal Clinical Cancer Research. The research is supported by a grant from the National Institutes of Health (P50 CA119997) and funds from the Moffitt Cancer Center Lung Cancer Center of Excellence. These studies were conducted in collaboration with researchers at the Tianjin Medical University in China.
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