共转导 DNR 的 B7H3 CAR-NK 细胞在外源 TGF-β 存在下保留抗 GBM 的细胞溶解功能

Cord blood (CB)-derived natural killer (NK) cells that are genetically engineered to express a chimeric antigen receptor (CAR) are an attractive off-the-shelf therapy for the treatment of cancer, demonstrating a robust safety profile in vivo . For poor prognosis brain tumors such as glioblastoma multiforme (GBM), novel therapies are urgently needed.

Although CAR-T cells demonstrate efficacy in preclinical GBM models, an off-the-shelf product may exhibit unwanted side effects like graft-versus-host disease. Hence, we developed an off-the-shelf CAR-NK cell approach using a B7H3 CAR and showed that CAR-transduced NK cells have robust cytolytic activity against GBM cells in vitro .

However, transforming growth factor (TGF)- within the tumor microenvironment has devastating effects on the cytolytic activity of both unmodified and CAR-transduced NK cells. To overcome this potent immune suppression, we demonstrated that co-transducing NK cells with a B7H3 CAR and a TGF- dominant negative receptor (DNR) preserves cytolytic function in the presence of exogenous TGF- .

This study demonstrates that a novel DNR and CAR co-expression strategy may be a promising therapeutic for recalcitrant CNS tumors like GBM.