Project summary: Chimeric antigen receptor T (CART) cells have transformed the cancer therapy paradigm by genetically engineering a patient's own T cells to specifically kill cells expressing the targeted antigen, such as CD19 for B cell malignancies. CART cell proliferation and formation of memory CART cells result in complete B cell depletion and durable remission of otherwise refractory B cell cancers. We re-designed CART technology for autoimmune disease therapy by utilizing an autoantigen as the extracellular domain of a chimeric autoantibody receptor (CAAR), linked to cytoplasmic T cell receptor costimulatory and activation domains. CAARs direct T cell cytotoxicity against autoantigen-specific B cells by targeting their B cell receptor, a surface-bound autoantibody identical in specificity to the autoantibody the B cell will secrete once activated to mature into a plasmablast. We established proof-of-concept for CAAR safety and efficacy in experimental models of pemphigus vulgaris (PV), a potentially fatal blistering disease caused by autoantibodies to the epithelial adhesion protein desmoglein 3 (DSG3). If CAARs for autoimmunity prove to be as effective as CARs for B cell cancers, CAAR T cells could represent a one-time treatment leading to autoimmune disease cure. An open-label, dose-escalation, first-in-human phase 1 trial to determine the safety and tolerability of DSG3 CAAR T cell therapy (DSG3-CAART) in mucosal-dominant pemphigus vulgaris has been initiated. DSG3-CAART is the first precision cellular immunotherapy for autoimmune disease to enter clinical trials, which presents a unique opportunity to define the immunomodulatory effects of this novel therapeutic approach in humans. DSG3-CAART is designed to specifically eliminate DSG3-reactive memory B cells that replenish the autoantibody-producing plasmablasts in PV. Depletion of anti-DSG3 memory B cells could remove a key driver of DSG3-specific T cell activation, and DSG3-CAART persistence may induce changes in global T cell subset composition and/or cytokine milieu, resulting in dual mechanisms for disease remission through both the B and T cell compartments. The proposal will evaluate the hypothesis that DSG3-CAART will reset immune tolerance in PV by depleting DSG3-reactive B cells and normalizing pathologic T cell subsets, potentially leading to safe and lasting disease remission.

Project narrative: Current therapies for autoimmune disease chronically suppress the immune system, which risks severe infection. DSG3-CAART is the first precision T cell immunotherapy for autoimmune disease to enter clinical trials, which presents a unique opportunity to investigate the immunomodulatory effects of this novel targeted therapeutic approach in humans. The proposed studies will elucidate the cellular and molecular determinants of DSG3-CAART activity and host immune response, using clinical samples collected from subjects enrolled in the DSG3-CAART phase 1 study.