Allogeneic“off-the-shelf”chimeric antigen receptor(CAR)T-cell therapy offers numerous advantages over autologous approaches.However,two critical challenges are encountered:graft-versus-host disease(GVHD)and poor per...Allogeneic“off-the-shelf”chimeric antigen receptor(CAR)T-cell therapy offers numerous advantages over autologous approaches.However,two critical challenges are encountered:graft-versus-host disease(GVHD)and poor persistence due to both extrinsic(host immune rejection)and intrinsic(TCR deletion-mediated)mechanisms.To prevent GVHD and prevent host-mediated graft rejection,allogeneic CAR-T-cell strategies typically employ selective editing of surface receptors or ligands,including(1)reducing the risk of GVHD by gene editing with TCR deletion[1,2];(2)diminishing allogeneic immunogenicity by knocking out HLA andβ2 m,which can alleviate T-cell-mediated immune rejection but inadvertently activates NK cells[3];and(3)preventing NK-cell-dependent lysis by overexpressing NK-inhibitory ligands,such as the nonclassical HLA molecules HLA-E and HLA-G[4].Recently,Wu et al.introduced a novel strategy that targets signal peptide peptidase-like 3(SPPL3)in allogeneic CAR-T cells.This approach confers dual resistance to both allogeneic rejection(mediated by T/NK cells)and Fas-dependent activation-induced cell death(AICD).Importantly,endogenous TCR expression was preserved,thereby enhancing CAR-T-cell persistence without increasing the risk of GVHD.In a phase 1 clinical trial,SPPL3-null CAR-T cells exhibited both safety and promising efficacy in patients with B-cell hematologic malignancies[5].展开更多
文摘Allogeneic“off-the-shelf”chimeric antigen receptor(CAR)T-cell therapy offers numerous advantages over autologous approaches.However,two critical challenges are encountered:graft-versus-host disease(GVHD)and poor persistence due to both extrinsic(host immune rejection)and intrinsic(TCR deletion-mediated)mechanisms.To prevent GVHD and prevent host-mediated graft rejection,allogeneic CAR-T-cell strategies typically employ selective editing of surface receptors or ligands,including(1)reducing the risk of GVHD by gene editing with TCR deletion[1,2];(2)diminishing allogeneic immunogenicity by knocking out HLA andβ2 m,which can alleviate T-cell-mediated immune rejection but inadvertently activates NK cells[3];and(3)preventing NK-cell-dependent lysis by overexpressing NK-inhibitory ligands,such as the nonclassical HLA molecules HLA-E and HLA-G[4].Recently,Wu et al.introduced a novel strategy that targets signal peptide peptidase-like 3(SPPL3)in allogeneic CAR-T cells.This approach confers dual resistance to both allogeneic rejection(mediated by T/NK cells)and Fas-dependent activation-induced cell death(AICD).Importantly,endogenous TCR expression was preserved,thereby enhancing CAR-T-cell persistence without increasing the risk of GVHD.In a phase 1 clinical trial,SPPL3-null CAR-T cells exhibited both safety and promising efficacy in patients with B-cell hematologic malignancies[5].
