Universal protection of allogeneic T-cell therapies from natural killer cells via CD300a agonism

• Published in: Blood advances 2024-10
• Main Authors: Zhang, Shu-Qi, Thomas, Faith, Fang, Justin, Austgen, Kathryn, Cowan, Chad, Welstead, G. Grant
• Format: Article
• Language: English
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2024013436

•An engineered CD300a agonist ligand (CD300a TASR) universally protects HLA-deficient allogeneic T cells from NK cell–mediated rejection.•CD300a TASR is more protective in cytomegalovirus seropositive hosts than HLA-E ligand and enhance chimeric antigen receptor T-cell efficacy under allogeneic immune pressure. [Display omitted] 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.