p:Hishing for T cells: Using ‘chimeric antigen-presenting’ (CAP) T cells to target and eliminate antigen-specific T cell populations 4027

Abstract Description Many autoimmune conditions are caused, in part, by T cell populations that target and damage ‘self’ tissue. It is therefore of therapeutic interest to eliminate such populations while leaving the healthy T cell repertoire intact. We hypothesize that by using disease-relevant peptide:HLA (p:H) domains as ‘bait’, we can engineer T cells to specifically target and eliminate self-reactive T cell populations for the treatment of autoimmune disease. To this end, we have engineered human T cells expressing chimeric, antigen-presenting “CAP” constructs consisting of a 1) p:H extracellular domain fused to the CD28 transmembrane and intracellular CD28/CD3z signaling domains, and 2) an engineered “di-sulfide trap” to stabilize p:H interactions and surface expression. As proof-of-concept, we successfully generated CD4 and CD8 human CAP T cells presenting HLA-A2 restricted antigens: YV9 (HIV), COL6A3 (pan-cancer), as well as target T cells engineered to express cognate TCRs. To assess killing, CAP T cells were co-cultured with specific or non-specific targets, or a mix of both. We found that CAP T cells efficiently eliminated >98% of target T cells expressing cognate TCRs within 72h. Importantly, CAP mediated-killing was specific, as minimal off-target effects were observed in mixed-target cultures. This work provides a proof-of-concept for CAP T cells, and demonstrates their potential for the generation of a novel T cell-based therapy to treat human autoimmune disease. Funding Sources Supported by the Colton Center for Autoimmunity and an Award from the Muriel Joan Drew Hege, MD, Fund for Women in Cellular Immunotherapy Research. Topic Categories Therapeutic Approaches to Autoimmunity (THER)