Chimeric Autoantibody Receptor- and/or Peptide-MHC-Based CAR Therapies for Targeted Elimination of Antigen-Specific B or T Cells in Hypersensitivity Disorders Such as Allergies and Autoimmune Diseases

Abstract

Hypersensitivity reactions are dysregulated and potentially devastating immune responses, characterized by a tendency to become chronic. They target either self-proteins or harmless foreign proteins and are driven by both T and B cells. Although numerous symptomatic treatment options for hypersensitivity reactions have been established over recent decades, only a few antigen-specific, causal approaches capable of specifically targeting the pathogenic autoreactive T and/or B cells have been developed. Among these are cell-based treatment modalities involving chimeric antigen receptor (CAR)- or chimeric autoantibody-receptor (CAAR)-expressing cells. These therapies utilize B- or T-cell antigens, presented as B-cell epitopes or peptide-major histocompatibility complexes (pMHCs) to serve as bait. The latter are coupled to potent activation domains derived from the TCR/CD3 complex itself, such as the zeta or CD3 chains, as well as domains from bona fide co-stimulatory molecules (e.g., CD28, 4-1BB). Recent in vitro and in vivo studies have demonstrated the therapeutic potential of these ATMP-based strategies in eliminating autoreactive lymphocytes and alleviating hypersensitivity reactions. This systematic review provides a comprehensive overview of the current status of antigen-specific CAR and CAAR T-cell therapies, highlighting novel directions as well as the ongoing challenges within this promising research field.

Keywords: CAAR; CAR; allergy; autoimmunity; chimeric antigen receptor; chimeric autoantigen receptor; hypersensitivity.

Figure 1

(A) Schematic structure of classical CARs, chimeric autoantibody receptor (CAAR), and peptide–MHC (pMHC)-based CARs. Classic CARs use a single-chain variable fragment (scFv) to recognize cell surface antigens. CAARs incorporate a (self-)antigen extracellular domain to selectively target autoreactive B cells. pMHC-based CARs present a peptide bound to MHC class II, enabling the targeting of antigen-specific CD4+ T cells via their TCR. (B) Overview of redirected cell-mediated killing strategies employed for redirecting cell-mediated cytotoxicity, including CAAR and pMHC-based CAR approaches, targeting autoreactive or allergen-specific T and B cells are illustrated. (C) Overview of possible toxicities associated with different CAR-based cellular immunotherapies.