# Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $369,009

## Abstract

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.

## Key facts

- **NIH application ID:** 10809735
- **Project number:** 5R01AR082675-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Aimee S Payne
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $369,009
- **Award type:** 5
- **Project period:** 2023-03-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809735

## Citation

> US National Institutes of Health, RePORTER application 10809735, Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris (5R01AR082675-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10809735. Licensed CC0.

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