Universal Cloaking of Allogeneic T Cell Therapies Against Natural Killer Cells Via CD300a Agonism

Immunogenicity limits the persistence of off-the-shelf, allogeneic cell therapies and transplants. While ablation of human leukocyte antigen (HLA) removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered Trans Antigen Signaling Receptors (TASR) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. When combined with an anti-CD19 Chimeric Antigen Receptor (CAR) using multiplexed non-viral integration, allogeneic primary T cells exhibited enhanced B cell killing potency under allogeneic immune pressure. Additionally, the expression of CD300a TASR on iPSC-derived T cells provided protection against alloreactive NK cells. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies, including iPSC-derived CAR T cells.