Abstract
Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells.
Highlights
Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers
While receptor downregulation is observed in both CARs and T cell receptor (TCR), the specific binding characteristics of CARs may result in a distinctive functional consequence known as “fratricide”, which is T cell death induced by neighboring CAR T cells due to targeting of the antigen expressed on T cells
We show that 'autotuning', a sensitivity tuning mechanism characterized by sustained CAR downregulation, endows MVR CAR T cells with target-cell selectivity based on antigen level
Summary
Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. The extent of downregulation was correlated with TCR–target affinity and, most importantly, eventually resulted in an increase in the overall immune-activation threshold This phenomenon represents a mechanism by which T cells tune antigen sensitivity and manage the extent of the immune response at the macro level. While receptor downregulation is observed in both CARs and TCRs, the specific binding characteristics of CARs may result in a distinctive functional consequence known as “fratricide”, which is T cell death induced by neighboring CAR T cells due to targeting of the antigen expressed on T cells. We show that human leukocyte antigen-DR (HLA-DR)targeted MVR CAR T cells continuously recognize HLA-DR on neighboring CAR T cells and induce fratricide and CAR downregulation. We show that 'autotuning', a sensitivity tuning mechanism characterized by sustained CAR downregulation, endows MVR CAR T cells with target-cell selectivity based on antigen level
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