Blood: The endogenous TCR expression of CD19-CAR-T cells?

Anti-CD19 encrusted antigen receptor (CAR) T cells exhibit significant anti-leukemia activity in B precursor acute lymphoblastic leukemia (ALL)A foreign, HLA mismatched off-the-shelf third-generation donor may provide ideal adaptability to the effect cells, but there is a risk of graft-resistant host disease (GVHD)Knocking out endogenous T-cell receptors (CRRs) of CD19-CAR-T cells may be a promising solutionIn this study, the researchers transduced the TC Rb chain with CRISPR/Cas9 medial in the primary T cells, combined with a second-generation retrovirus CAR containing a 4-1BB co-stimulating domainAfter the above treatment, the researchers obtained a highly functional TCR-KO-CAR-T cell group with strong activation (CD25, IFN-mouse serum), proliferation and specific killings for CD19 target recognitionTCR-KO-CAR-T cells have a balanced phenotype of central memory and effect memory T cellsKnocking out T-cell endogenous TCR strongly reduces the foreign reactivity compared to T cells expressing TCRIn an all-child xenotransplant model, TCR-KO-CAR-T cells clearly controlled the burden of CD19 plus leukemia, improving the survival rate of transplanted small cellsHowever, co-expression of endogenous TCR and CAR can provide excellent persistence of T cells and significantly prolong the inviviable control time of leukemia, as demonstrated in the second in vivo model using NALM6 leukemia cellsThe above results suggest that endogenous TCR plays an important role in reaction lifeIn summary, the anti-CD19 CAR T cells of the CRISPR/Cas9-mediated TCR KO are highly promising choices for non-matching third-party secondary T-cell transplantation, which has high anti-leukemia function without all-out allogeneic reactions, but has better in vivo response persistence when presented with endogenous TCR expression