Chimeric antigen receptor (CAR) T cell therapy is a; g4 w$ t) l# U3 j5 |
promising approach to treat cancer, such as B-cell malignancy : T! U% X6 J U2 \# ^- _, x* F5 Q[1]. However, the current standard treatment # n2 f, g4 h/ ~( `requires autologous adoptive cell transfer, which is expensive# M( ?) E2 R! R8 P" D
and time-consuming. For newborn and elder , d3 v( @% c; t3 }patients, it is often difficult to obtain enough T cells with " Z2 o& l" u+ t# t! x) d5 ^good quality to generate patient-specific CAR-T cells.8 `* R$ W1 x9 w( h' v" u
To make CAR-T therapy more accessible, it is highly: T( s' w- [$ `" G; c
desirable to develop an allogeneic adoptive transfer 1 q7 N) G7 p9 p' {4 tstrategy, in which universal CAR-T cells derived from T$ E5 i6 z U j5 S; \+ S( t
cells from healthy donors can be applied to treat multiple- h+ L% {+ G( ]. V
patients. For this strategy to work, the αβ T-cell receptor & E# E& S4 \9 w(TCR) on allogeneic CAR-T cells needs to be eliminated( h h( b7 ^4 A; E" {! J1 W' m, g
to avoid graft-versus-host-disease (GVHD), and human , f7 g% q+ s& B3 Jleukocyte antigens class I (HLA-Is) on CAR-T cells need9 B8 X* ?+ u+ }2 w5 b
to be removed to minimize their immunogenicity. Previous K9 }( e- }2 O& d' z& g
studies have shown that mutation in TCRα subunit & z+ Z/ }: p9 X+ k8 D# ]& f# @constant (TRAC) leads to loss of αβ TCR on T-cell surface" Z$ k' I) Z" e- t8 E" I+ S
[2], and beta-2 microglobulin (B2M) is essential for . N7 Q$ I" i- q/ Q7 X6 n- G6 Gcell-surface expression of HLA-I heterodimers [3]. Thus,& N5 R9 {6 ]3 _" ]2 o
we attempted to target TRAC and B2M genes in CAR-T. v# g9 _/ `$ l. J3 B" [$ n' K' n
cells. Considering blocking programmed death-1 (PD-9 t: E' ^" G& l2 Q0 d4 U
1) signaling can effectively treat cancers via reversing" Y3 f! v6 f; t- l: L
immunosuppression, we also targeted PD-1 in CAR-T $ Z4 p( \% e0 I5 j' Bcells to render them nonresponsive to PD-1 signaling