| 摘要: |
Chimeric antigen receptor (CAR) T cell therapy is a promising approach to treat cancer, such as B-cell malignancy1. However, the current standard treatment requires autologous adoptive cell transfer, which is expensive and time-consuming. For newborn and elder patients, it is often difficult to obtain enough T cells with good quality to generate patient-specific CAR-T cells. To make CAR-T therapy more accessible, it is highly desirable to develop an allogeneic adoptive transfer strategy, in which universal CAR-T cells derived from T cells from healthy donors can be applied to treat multiple patients. For this strategy to work, the αβ T-cell receptor (TCR) on allogeneic CAR-T cells needs to be eliminated to avoid graft-versus-host-disease (GVHD), and human leukocyte antigens class I (HLA-Is) on CAR-T cells need to be removed to minimize their immunogenicity. Previous studies have shown that mutation in TCRα subunit constant (TRAC) leads to loss of αβ TCR on T-cell surface2, and beta-2 microglobulin (B2M) is essential for cell-surface expression of HLA-I heterodimers3. Thus, we attempted to target TRAC and B2M genes in CAR-T cells. Considering blocking programmed death-1 (PD-1) signaling can effectively treat cancers via reversing immunosuppression, we also targeted PD-1 in CAR-T cells to render them nonresponsive to PD-1 signaling4... |