A specific class of FDA-approved oncology agents called histone deacetylase (HDAC) inhibitors proved effective to induce T-cell responses in tumors, in conjugation with immunotherapeutic PD-1 antibodies, decreasing the growth of lung tumors in mice.
These findings suggest that combining HDAC inhibitors with PD-1 blockade could be a promising strategy for lung cancer treatment.
The research paper, “HDAC inhibitors enhance T cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma,” was published in Clinical Cancer Research.
Immunotherapeutic antibodies target and inhibit a variety of checkpoint receptors on the surface of T-cells, reactivating their capacity to target cancer cells. Despite numerous new immunotherapeutic antibodies approved for the treatment of advanced-stage lung cancer and melanoma, a significant limitation of checkpoint blockade immunotherapy is its relatively low response rate, with only about 20 percent of lung cancer patients demonstrating a response to PD-1 blockade. This low response rate has been blamed on the small number of T-cells within the tumor micro-environment.
Researchers at Moffitt Cancer Center in Tampa, Florida, screened 97 FDA-approved oncology agents with the ability to enhance T-cell chemokine expression — chemical messengers that stimulate T-cell infiltration into tumors to identify agents that could enhance immunotherapeutic responses.
The oncologic agents were tested in lung tumor models, both as mono and combination therapy with anti-PD-1 antibodies. One class of drugs, the histone deacetylase inhibitors, emerged as capable of inducing T-cell chemokine expression in vitro. And, in vivo use of HDAC romidepsin led to increased chemokine expression, enhanced T-cell infiltration, and T-cell dependent tumor regression. Romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models.
These results pave the way for a new clinical application of HDAC inibitors, since so far their use as single agents in solid tumors has not produced positive results. “These results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment,” senior author Amer Beg said in a press release.
A clinical trial is currently recruiting participants to test combination therapy of an HDAC and PD-1 inhibitor in stage 4 non-small cell lung cancer patients.