Universal protection of allogeneic T-cell therapies from natural killer cells via CD300a agonism
Year: 2024
Type: article
Abstract: Immunogenicity limits the persistence of off-the-shelf allogeneic cell therapies and transplants. Although ablation of 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 (TASRs) 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. A model allogeneic T-cell therapy coexpressing an anti-CD19 chimeric antigen receptor and CD300a TASR, produced using multiplexed nonviral integration, exhibited enhanced B-cell killing potency under allogeneic immune pressure. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies.
Source: Blood Advances
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
OpenAlex ID: W4403151870