Clinical and translational data from a first-in-human study of a novel precision cellular immunotherapy (DSG3-CAART) in mucosal pemphigus vulgaris

Summary: Abstract Body: Mucosal pemphigus vulgaris (mPV) is an autoimmune disease caused by autoantibodies to the epithelial adhesion protein desmoglein 3 (DSG3). As a precision medicine approach for mPV, chimeric autoantibody receptor T cell (CAART) technology was developed using an autoantigen-based synthetic immunoreceptor designed to direct T cell cytotoxicity only against anti-DSG3 autoantibody-expressing B cells to avoid global B cell depletion. 23 mPV subjects were enrolled in an open-label phase 1 study of DSG3-CAART, employing 6 dose-escalation cohorts without preconditioning plus 2 cohorts with preconditioning. One subject experienced grade 1 cytokine release syndrome. No dose-limiting toxicities occurred. DSG3-CAART persistence increased linearly across the first 4 cohorts then plateaued; preconditioning with IVIg, cyclophosphamide, +/- fludarabine did not increase post-infusion persistence. After infusion, a decrease in CAAR mean fluorescence intensity was observed in all subjects, associated with enrichment of stem cell memory-like immunophenotypes, little to no IFN-gamma secretion, and no consistent pattern of improvement in clinical disease activity scores or anti-DSG3 antibody titers. In cytotoxicity assays, CAARTs with low CAAR expression demonstrated inferior cytolytic activity compared to those with high CAAR expression. Collectively, these first-in-human data indicate DSG3-CAART is well tolerated, but suggest low CAAR expression post-infusion, potentially due to soluble antibody internalization or inhibition, may impact clinical efficacy. Aimee S. Payne³, D Nunez⁴, JR Volkov⁴, DJ Thompson⁴, ME Werner⁴, JE Stadanlick⁴, L Ishikawa⁴, J Cicarelli⁴, Q Lam⁴, CM Miller⁴, KA Sheipe⁴, SM Vieira², DL Porter², Robert Micheletti², Emanual Maverakis¹, M Abedi¹, Janet A. Fairley⁵, U Farooq⁵, MP Marinkovich⁶, WK Weng⁶, A Dominguez⁷, O Pacha⁸, Alan Zhou⁹, J Mehta⁹, MM Shinohara¹⁰, DG Maloney¹⁰, MC Milone², GK Binder⁴, DJ Chang⁴, S Basu⁴ 1. UC-Davis, Davis, CA, United States. 2. Univ of Pennsylvania, Philadelphia, PA, United States. 3. Columbia Univ, New York, NY, United States. 4. Cabaletta Bio, Philadelphia, PA, United States. 5. Univ of Iowa, Iowa City, IA, United States. 6. Stanford Univ, Stanford, CA, United States. 7. UT-Southwestern, Dallas, TX, United States. 8. MD Anderson Cancer Center, Houston, TX, United States. 9. Northwestern Univ, Chicago, IL, United States. 10. Univ of Washington, Seattle, WA, United States. Clinical Research: Interventional Research