HDAC inhibitor (SAHA) enhances B7-H3-specific CAR T cell cytotoxic efficacy against chondrosarcoma cells and prolongs survival in an orthotopic mouse model

Abstract

High-grade Chondrosarcoma (Grades II, III, and dedifferentiated) is an aggressive primary malignant bone tumor characterized by hyaline cartilaginous neoplastic tissue without any effective systemic therapy. Localized disease is treated with a complete surgical resection with negative margins. However, high-grade chondrosarcoma often spreads systemically, leading to low overall survival rates of 29 %. These clinical findings emphasize the urgent need for improved systemic therapies. Among them is chimeric antigen receptor (CAR) T cell therapy. In this study, tumor-associated antigen B7-H3, which is highly expressed in chondrosarcoma cells but has a restricted expression in normal tissues, is targeted with B7-H3-specific CAR T cells. Our results show that these CAR T cells are effective in killing chondrosarcoma cells in vitro and retard chondrosarcoma tumor growth in immunodeficient mice, which resulted in prolonged survival of tumor-bearing mice. To enhance the antitumor activity of B7-H3 CAR T cells, tumor cells or CAR T cells were treated ex-vivo with a low dose of vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor that upregulates B7-H3 transcription and expression in several types of solid cancer cells as well as the chimeric antigen receptor. Our results demonstrate that treatment of B7-H3 CAR T cells or chondrosarcoma cells with SAHA enhances CAR T cell antitumor cytotoxic activity in vitro and in vivo.