Allogeneic CAR-T Cells: Engineering Around Host Immunity

Allogeneic (“off-the-shelf”) CAR-T cells promise faster treatment access, standardized manufacturing, and scalable supply compared with autologous products, but they face a core biological constraint: the recipient immune system recognizes allogeneic CAR-T as a graft and eliminates it, while residual donor T-cell receptor (TCR) activity can cause graft-versus-host disease (GvHD). Clinical progress over the last several years has validated feasibility, with encouraging response rates in B-cell malignancies and generally manageable safety profiles, yet persistence and repeat dosing remain limited by host-versus-graft (HvG) immunity. For example, a peer-reviewed report of allogeneic anti-CD19 CAR-T in LBCL described measurable expansion, persistence up to months, and objective responses in heavily pretreated patients. This mini-review focuses on an increasingly central barrier: humoral rejection (donor-specific antibodies, complement, and Fcγ receptor–dependent effector mechanisms), alongside cellular rejection (host T cells, NK cells, and macrophages) and the “missing-self” problem created by HLA class I ablation. We summarize the current engineering playbook—TCR disruption to prevent GvHD, HLA editing and inhibitory ligand strategies to evade cellular HvG, and emerging concepts to resist antibody-mediated killing—and propose a practical design logic for next-generation allogeneic CAR-T: multi-layer immune evasion without forfeiting antitumor function or manufacturability.