Histone Deacetylase Inhibitors Shown to Restimulate T Cells, Improve Immunotherapy in Lung Cancer
Histone deacetylase (HDAC) inhibitors improve the activity of immunotherapeutic antibodies in cell culture and mouse models of lung cancer. HDAC inhibitors achieve this by restimulating T cells to move into a tumor. Once in the tumor, the activity of the T cells is enhanced.1
Several immunotherapeutic antibodies have been FDA-approved for the treatment of advanced lung cancer and for melanoma, but only 20% of patients with lung cancer respond to these antibodies. Immunotherapeutic antibodies block checkpoint receptors of T cells, allowing T cells to attack tumors. In particular, antibodies that inhibit PD-1 can restimulate these T cells because blocking PD-1 prevents tumors from evading the immune system.
In this study, published in Clinical Cancer Research, researchers screened 97 FDA-approved oncologic compounds for agents that could enhance T cells. Researchers were looking for agents that could enhance PD-1 blocking antibodies. They determined which compounds could do this by looking for agents that increased the expression of chemokines, because chemokines promote T cell invasion into tumors.
This study found romidepsin, an HDAC inhibitor, enhanced T cell invasion of the tumor and increased tumor regression in mice. When romidepsin was administered in conjunction with a PD-1 blockade therapy, the activation of tumor-infiltrating T cells significantly increased. These results were observed across multiple mouse and cell culture models of lung cancer.
"These results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment," said Amer Beg, PhD, professor in the Immunology Program at University of South Florida H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, and lead author of the study.
The H. Lee Moffitt Cancer Center and Research Institute has started a clinical trial to test the combination of an HDAC inhibitor and PD-1 inhibitor for stage IV non-small cell lung cancer. The trial is currently recruiting participants.
1. Zheng H, Zhao W, Yan C, et al. HDAC inhibitors enhance T cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma [published online ahead of print March 10, 2016]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-15-2584.