Chimeric antigen receptor T cell therapy for autoimmune disease

Abstract

Infusion of T cells engineered to express chimeric antigen receptors (CARs) that target B cells has proven to be a successful treatment for B cell malignancies. This success inspired the development of CAR T cells to selectively deplete or modulate the aberrant immune responses that underlie autoimmune disease. Promising results are emerging from clinical trials of CAR T cells targeting the B cell protein CD19 in patients with B cell-driven autoimmune diseases. Further approaches are being designed to extend the application and improve safety of CAR T cell therapy in the setting of autoimmunity, including the use of chimeric autoantibody receptors to selectively deplete autoantigen-specific B cells and the use of regulatory T cells engineered to express antigen-specific CARs for targeted immune modulation. Here, we highlight important considerations, such as optimal target cell populations, CAR construct design, acceptable toxicities and potential for lasting immune reset, that will inform the eventual safe adoption of CAR T cell therapy for the treatment of autoimmune diseases.

Fig. 1|. Expression of protein markers during B cell development and differentiation.

B cells arise in the bone marrow and exit into the periphery as they mature. B cells differentiate into antibody-secreting plasma cell populations, which include short-lived plasmablasts and long-lived plasma cells that reside in the bone marrow. CD19, CD20, CD38 and B cell maturation antigen (BCMA) are surface proteins expressed at various stages of development and differentiation that enable identification of distinct B cell subsets and serve as therapeutic targets for the treatment of autoimmune diseases.

Fig. 2|. Key components of chimeric antigen receptors (CARs).

CARs include an extracellular antigen-recognition domain that is usually a single-chain variable fragment (scFv). This domain imparts antigen specificity to the CAR. Types of antigen-recognition domain include scFvs or other antibody-based domains targeting proteins such as CD19 or B cell maturation antigen (BCMA). Binding domains can also be the target protein of autoantibodies (i.e., autoantigens). The antigen-recognition domain is connected to intracellular signalling domains by hinge and transmembrane domains. The intracellular signalling domains comprise a costimulatory domain, such as CD28 or 4–1BB, and a T cell activation domain that is usually from CD3ζ. ITAM, immunoreceptor tyrosine-based activation motifs.

Fig. 3 |. Select types of chimeric antigen receptor (CAR) constructs.

a, In the monospecific standard CAR, a single-chain variable fragment (scFv) extracellular antigen-recognition domain is connected by a hinge and transmembrane (HTM) domain to a costimulatory domain and a T cell activation domain. b, A T cell transduced with a bicistronic CAR construct simultaneously expresses two different CARs that are encoded by one gene therapy vector. The CARs contain different scFvs and can also have different intracellular signalling domains. c, A T cell receptor (TCR) fusion construct (TRuC) has scFvs that are fused to one of the endogenous TCR subunits. In this example, the scFvs are fused to the ε-chains of the TCR. Other chains of the endogenous TCR participate in the complex as shown. d, An armoured CAR includes a T cell expressing a CAR together with a separate protein. For example, an armoured CAR construct could encode a CAR along with an immunologically active cytokine. e, Chimeric autoantibody receptor (CAAR) T cells express a CAR with a binding domain made of the target protein of autoantibodies (autoantigen). The goal of this approach is to selectively eliminate autoreactive B cell clones when their B cell receptors engage the autoantigen that makes up the extracellular part of a CAAR expressed by the T cell.

Fig. 4|. Engineered regulatory T cell properties.

A regulatory T (T_reg) cell, either as a natural T_reg cell or CD4⁺ T cell engineered to express FOXP3, can be further transduced with homing receptors (such as chemokine receptors or integrin cell surface molecules), a chimeric antigen receptor (CAR) directed against a tissue-specific target antigen, such as mucosal vascular addressin cell adhesion molecule 1 or flagellin to favour gut tropism or CXC-chemokine ligand 12 to favour bone marrow tropism, or a T cell receptor (TCR) specific for a disease-driving epitope, leading to tissue-specific localization (for example, the gut in the case of inflammatory bowel disease). Upon activation through CAR or engineered TCR engagement, the T_reg cell exerts local immunosuppression through soluble mediators and cell–cell interactions. The T_reg cell can be further engineered to deliver a custom payload, building upon intrinsic properties by increasing immunomodulation (for example, adding genes encoding interleukin-10 or amphiregulin). CTLA4, cytotoxic T lymphocyte associated protein 4.