allogeneic CRISPR-edited anti-CLL-1 CAR-T cells CB-012

A preparation of allogeneic, off-the-shelf T lymphocytes genetically modified and clustered regularly interspaced short palindromic repeats (CRISPR)-edited to contain the deletion of the TRAC gene, the site-specific insertion of a chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) C-type-lectin-like molecule-1 (CLL-1; CLL1; C-type lectin domain family 12 member A; CLEC12A; CD371) into the TRAC gene, the knockout of programmed death 1 (PD-1; PDCD1; CD279; programmed cell death-1), the deletion of the B2M gene, and the site-specific insertion of a gene encoding a B2M-HLA-E-peptide fusion into the B2M gene, with potential immunostimulating and antineoplastic activities. Upon administration, allogeneic CRISPR-edited anti-CLL-1 CAR-T cells CB-012 recognize and bind to CLL-1-expressing tumor cells. This may result in a specific cytotoxic T-lymphocyte (CTL)-mediated killing of CLL-1-expressing tumor cells. Knock out of the TRAC gene eliminates the endogenous T-cell receptors (TCRs), thereby preventing graft-versus-host disease (GvHD). PD-1, an immune checkpoint receptor expressed on T cells, plays a key role in tumor immune evasion by binding to its ligand programmed death ligand 1 (PD-L1; cluster of differentiation 274; CD274; programmed cell death-1 ligand 1) expressed on tumor cells. By removing PD-1 from T cells, PD-1-mediated signaling is halted which may decrease T-cell exhaustion and may enhance T-cell activity against the CLL-1-expressing tumor cells. The B2M protein is removed to eliminate endogenous HLA class I expression on the surface of the CB-012 CAR-T cells, which protects the CAR-T cells from host T-cell rejection. The B2M-HLA-E fusion protein is inserted to protect the CAR-T cells from host natural killer (NK) cell rejection. CLL-1, a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily, is overexpressed in leukemic stem cells (LSCs) and plays an important role in disease progression and relapse for myeloid malignancies.