Entinostat, a histone deacetylase inhibitor, enhances CAR-NK cell anti-tumor activity by sustaining CAR expression

Area of Science:

• Immunology
• Cancer Therapy
• Cell Biology

Background:

• Allogeneic natural killer (NK) cell therapy shows promise in cancer immunotherapy.
• Chimeric antigen receptor (CAR)-engineered NK cells targeting CD138 are a potential treatment for multiple myeloma (MM).
• Maintaining CAR expression on CAR-NK cells during ex vivo expansion is a significant challenge for effective immunotherapy.

Purpose of the Study:

• To investigate the use of histone deacetylase inhibitors (HDACi) to enhance and stabilize CAR expression in CAR-NK cells.
• To evaluate the impact of entinostat (ENT), an HDACi, on the anti-myeloma activity of CD138-targeting CAR-NK cells.

Main Methods:

• Primary NK cells were isolated, cryopreserved, and engineered to express anti-CD138 CARs via retroviral transduction.
• Entinostat (ENT), a histone deacetylase inhibitor, was used to treat the engineered CAR-NK cells.
• CAR expression stability, cytotoxic activity against CD138-positive MM cells, and in vivo efficacy in a mouse model were assessed.

Main Results:

• ENT treatment significantly improved and maintained CAR expression on CAR-NK cells.
• ENT-treated CAR-NK cells demonstrated enhanced cytotoxic activity against multiple myeloma cells.
• In vivo studies showed prolonged persistence and significant tumor reduction in MM-bearing mice treated with ENT-treated CAR-NK cells.

Conclusions:

• Histone deacetylase inhibitors, specifically entinostat, can sustain CAR expression in CAR-NK cells in a promoter-dependent manner.
• HDACi treatment enhances the anti-tumor efficacy of CAR-NK cells against multiple myeloma.
• This approach holds therapeutic potential for multiple myeloma and warrants further clinical investigation.