Researchers at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD, have discovered a new combination of drugs that helped immunotherapy drugs respond better to non-small cell lung cancers (NSCLC). The results were published in Cell.
The findings demonstrated that these so-called epigenetic therapy drugs, when used in combination, achieved robust anti-tumor responses in human cancer cell lines as well as in mouse models.
Investigators were led by graduate student Michael Topper, research associate Michelle Vaz, PhD, and senior author Stephen B. Baylin, MD. The team devised a new, low-dose regimen of DNA-demethyltransferase inhibitors (DNMTIs) combined with histone deacetylase inhibitors (HDACIs) that resulted in a dramatic anti-tumor effect.
“Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T-cell exhaustion state towards memory and effector T-cell phenotypes,” the authors wrote.
Researchers combined 5-azacytidine with one of the three HDACIs—entinostat, mocetinostat, or givinostat—in human cancer cell lines and in mouse models of NSCLC. The result lead to an altering of the tumor microenvironment.
In cancer cell lines, 5-azacytidine worked against the cancer gene MYC, causing downregulation of the MYC signaling program. Adding the HDACIs further depleted MYC, and together the drugs subsequently caused actions that prevented cancer cell proliferation, simultaneously attracted more immune system T-cells to the area of the tumor, and activated these cells for tumor recognition.
“In our study, the two-drug epigenetic therapy combination worked exceedingly well, even before putting in the immune checkpoint inhibitors,” Dr. Baylin explained. “In animal models of lung cancer, the two agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”
In mouse models, 5-azacytidine combined with givinostat resulted in the strongest response. Moreover, a regimen alternating givinostat and mocetinostat with 5-azacytidine reduced the growth of established, rapidly growing primary tumors and dramatically reduced metastasis in mice with established, aggressive NSCLC.
Encouraged by the results of this study, Dr. Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia, PA, are conducting a clinical trial to determine if mocetinostat plus guadecitabine, a drug similar to 5-azacytidine, can boost immune checkpoint therapy responses in patients with NSCLC.
To read more about this study, click here.