Mutant B2M-HLA-E and B2M-HLA-G fusion proteins protects universal chimeric antigen receptor-modified T cells from allogeneic NK cell-mediated lysis.

Abstract

Recent studies have indicated the antitumor activity and reduced allogeneic response of universal chimeric antigen receptor‐modified T (UCAR T) cells lacking endogenous T cell receptors and beta‐2 microglobulin (B2M) generated using gene‐editing technologies. However, these cells are vulnerable to lysis by allogeneic natural killer (NK) cells due to their lack of human leukocyte antigen (HLA) class I molecule expression. Here, constitutive expression of mutant B2M‐HLA‐E (mBE) and B2M‐HLA‐G (mBG) fusion proteins in anti‐CD19 UCAR T (UCAR T‐19) cells was conducted to protect against allogeneic NK cell‐mediated lysis. The ability of cells expressing mBE or mBG to resist NK cell‐mediated lysis was observed in gene‐edited Jurkat CAR19 cells. UCAR T‐19 cells constitutively expressing the mBE and mBG fusion proteins were manufactured and showed effective and specific anti‐tumor activity. Constitutive expression of the mBE and mBG fusion proteins in UCAR T‐19 cells prevented allogeneic NK cell‐mediated lysis. In addition, these cells were not recognizable by allogeneic T cells. Additional experiments, including those in animal models and clinical trials, are required to evaluate the safety and efficacy of UCAR T‐19 cells that constitutively express mBE and mBG.