Cell therapy targeting follicular T cells as an innovative approach for treating autoimmune disease

Abstract

Abstract Systemic lupus erythematosus (SLE) is a debilitating and incurable autoimmune disease characterized by the uncontrolled production of autoantibodies and inflammatory damage to multiple organ systems. Dysregulated follicular helper T cell (TFH) responses are a cardinal feature and putative driver of disease in both mice and humans, where these cells contribute to unrestrained inflammation and autoantibody production by B cells. There is currently no safe and effective way to selectively eliminate TFH as a means to therapeutically alleviate diseases caused by these cells. Although cell surface biomarkers that are unique (lineage-specific targets) to TFH remain undefined, these cells express markedly more programmed cell death protein 1 (PD-1) than other immune cells. We recently engineered a novel programmed death-ligand 1 (PD-L1)-based chimeric antigen receptor (CAR) that when expressed on human natural killer (NK) cells, facilitated discriminate targeting of PD-1high follicular T cells while sparing other PD-1-expressing lymphocytes. The inherent specificity of this approach lies in the lower affinity interactions between PD-L1 and PD-1 compared to that likely achieved with a PD-1-specific single-chain variable fragment-based CAR. Here, we develop a mouse T cell version of the PD-L1 CAR platform to show that selective depletion of PD-1high T cells is safe and effective at undermining harmful autoreactive T and B cell responses in mouse models of SLE-like disease. We believe this affinity-based CAR approach for PD-1high target cell elimination represents a novel clinical tool for treatment of TFH-driven diseases like SLE.