Autoimmunity as a target for chimeric immune receptor therapy: A new vision to therapeutic potential

Abstract

Chimeric immune receptors (CIRs) are functionally pleiotropic because they are artificially expressed on diverse cell types, which gives specificity to their function to anergize, kill, or protect cognate target cells. CIRs consist of chimeric antigen receptors (CARs) and B-cell antibody receptor (BAR) or chimeric autoantibody receptors (CAARs). Approval of CAR-T cell therapy by the Food and Drug Administration (FDA) has encouraged investigators to search for autoimmune therapies that are CIR-based. Both T effector cells, particularly CD8⁺, and T CD4⁺ regulatory cells (Tregs) can be engineered through CIR expression. Recently, natural killer cells have been included to increase efficiency. Unwanted antibody producer B cells are effectively prevented by CAAR-T cells, B-cell antibody receptor (BAR)-T CD8+, and BAR-Treg, which represents an advantage in antibody-mediated diseases such as pemphigus vulgaris (PV) and hemophilia A. Although CAAR and BAR-T cells may have curative benefits for autoantibody-mediated immune diseases, verification of long-term efficacy and safety are a priority before clinical use. Effective CIR-T cell therapy largely depends on the reliability and stability of the receptor. Based on CIR functionality, factors that explicitly determine effectiveness of the treatment should be considered. These factors include antigen/autoantibody specificity, single chain variable fragment (scFv) affinity, and autoantibody masking. Herein, we review the current evidence of CIR therapy with a focus on their therapeutic potential for autoimmune diseases and their challenges.

Introduction

Adaptive T cell therapy is a new and rapidly developing area in cell therapy in which the adoptive transfer of genetically reprogrammed T cells, such as TCR transgenic cells and chimeric immune receptors (CIRs), has received more attention because they form recombinant or new receptors that can improve specific-antigen recognition [1].

TCR transgenic structures are designed to enhance affinity of the TCR for peptide-MHC. In TCR engineering T cell therapy, antigen specificity is determined by the new TCR heterodimer-mediated signaling pathway. However, during TCR engineering, more and sustainable responses are achieved when retroviral or lentiviral vectors are used to molecularly clone TCR-α and -β subunits from highly reactive T cells [1,2]. TCR engineering is a tool that can be used to augment T cells. TCR engineered T effector cells (Teff) are designed to target disruption, whereas TCR engineered regulatory T (Treg) cells can anergize/kill and protect target cells [3].

Although TCR engineering T cell therapy is a promising strategy to induce defined antigen-specific immune responses, limitations to their use include MHC-polymorphism, peptide antigens, unpredictable mixed TCR dimers, and TCR cross-reactivity against related or unrelated antigens [2].

CIR-T cells are of tremendous interest in T cell therapies for hematopoietic and solid malignancies, and immune-mediated diseases. Advantages of CIR-T cells include increased specificity and sensitivity to target cells, their non-MHC dependent manner, and extended safety [4].

The privileged activation of T cells following stimulation of CIR make them promising in an MHC-independent manner, which gives them a universal therapeutic use and superiority to TCR-based T cell therapies [4,5].

Generally, CIRs have two functional domains and a transmembrane region that fit the task to accomplish and are involved in signal transduction. The extracellular domain consists of a chopped fragment of a monoclonal antibody called a single chain variable fragment (scFv) in CAR or a specific antigen in CAAR, which can be a bio-therapeutic agent in a BAR system [6]. These domains bind to target antigens that are relatively specific for cells, tissues, and organs and to autoantibodies in CARs and BARs. Fig. 1 provides a summary of different CIR-T cells, including CAR-Treg and BAR-Teffs that protect normal cells. At the other end of the CIRs, signal transduction is initiated through the TCR domain. Thus, it becomes clear that CD3ζ plays a prominent role in the CIR system and other members can be exchanged for improvement without attenuating its function [7].

The lack of tissue-specific localization and antigen-specific detection substantially influences therapies for autoimmune diseases. These can be affected by CIR-T cells, resulting in eventual disruption or protection of targeted cells in various autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes (T1D), colitis, rheumatoid arthritis (RA), and pemphigus vulgaris (PV) [8]. In terms of antigen-specific T cells for autoimmune diseases, the CIR system can be categorized into BAR-T cells and CAR-Tregs that exogenously express CIR [9,10].

While CAR-T CD8+ professionally kill the tumor cells, the purpose of CIR-T cell therapy for autoimmune diseases is to provide direct protection of normal cells by CAR-Tregs and/or indirect protection by BAR-T cells (Fig. 2) [6,[10], [11], [12]].

Recently, CIR engineered T cells have been introduced as a protective factor against antibody-mediated responses in bio-therapeutics such as FVIII [12]. Zhang et al. conducted a CIR-based intervention to suppress antibody-mediated responses to factor VIII (FVIII) through BAR-Treg-mediated FVIII-specific B-cell suppression [12]. The FVIII-specific antibody response decreased through two distinct mechanisms, FVIII-specific B cells that were directly tolerized to the suppressive activity of FVIII-specific BAR-Tregs by currently unknown mechanisms and via indirect suppression of B cell function through suppression of T effector cells, which are essential for B cell activation [12]. Another aspect of B cell suppression was reported by Parvathaneni and Scott [6]. They used FVIII-specific BAR-CD8⁺ T cells to directly eliminate FVIII-specific B cells [6]. However, these evidences led to the conclusion that remarkable suppression of unwanted antibody production was due to BAR-Treg and BAR-T CD8⁺ therapy [6,12]. Clearly, it would be useful for future prophylactic treatment of patients who receive bio-therapeutic drugs such as FVIII. These results have suggested that B cell-mediated antibody responses can be controlled by BAR T cell system like dominant responses that occurred during antibody-mediated autoimmune diseases.

Although there are numerous clinical reports of CIR-T cell therapy in hematopoietic and solid tumor malignancies [[13], [14], [15], [16]], only preclinical studies have assessed the effect of CIR-T cells on a few autoimmune diseases. One clinical trial evaluated the induction of immune tolerance by polyclonal Tregs exclusively in new onset T1D, it and other ongoing trials listed in Table 1 [17].