Inhibiting PARP-11 to improve CAR T therapy in solid tumors

Inhibiting the mono-ADP-ribosylation enzyme PARP-11 could improve CAR T cell therapy against solid tumors by preventing immunosuppressive, adenosine-induced downregulation of IFNAR1. In CD8⁺ T cells from colorectal cancer patients, PARP-11 expression was lower in highly active CD103⁺CD39⁺ subpopulations than in naive or less active effector memory subsets.

In co-cultures with cell lines expressing mesothelin or CD19 as model antigens, antigen-targeted CAR T cells derived from PARP-11 knockout mice expressed higher levels of IFNAR1 and induced more target cell killing than CAR T cells with normal PARP-11 expression. In a mouse model of melanoma expressing CD19, shRNA knockdown or CRISPR knockout of PARP-11 in CD19-targeted CAR T cell decreased tumor growth and increased survival. ...