REGNASE-1 Gene Knockout or BATF Overexpression for Improving T-cell Function (SJ-19-0027, SJ-20-0007)

In patients, poor persistence and function of adoptively transferred cells are major obstacles for T cell-based tumor therapies. St. Jude researchers demonstrated that by knocking out REGNASE-1, which is identified in an in vivo CRISPR discovery platform, CD8 T cell long-term persistence is greatly improved (up to 2000x), and these cells are resistant to functional exhaustion and retain robust effector function. Strikingly, REGNASE-1 deficient CD8 T cells have greatly improved ability in controlling both solid and blood cancers; making it useful in engineered T cell, including CAR-T cell, based tumor immune therapy, and potentially, regulatory T cell (Treg) based immune therapy in autoimmune diseases. Additional factors were identified to act alone or in combination with REGNASE-1 deletion to improve T-cell function.

The researchers also discovered that by overexpressing one single molecular (BATF; Basic Leucine Zipper ATF-Like Transcription Factor), the accumulation and effector function of tumor-specific T cells are markedly enhanced. This is useful for immunotherapy against solid and blood cancers using CAR-T and other engineered T cells.