CAR T cells for treating autoimmune diseases

Abstract

Autoimmune disorders occur when immune cells go wrong and attack the body's own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive agents and blocking antibodies, which can manage the diseases but often are not curative. Thus, there is an urgent need for advanced therapies for patients suffering from severe and refractory autoimmune diseases, and researchers have considered cell therapy as potentially curative approach for several decades. In the wake of its success in cancer therapy, adoptive transfer of engineered T cells modified with chimeric antigen receptors (CAR) for target recognition could now become a therapeutic option for some autoimmune diseases. Here, we review the ongoing developments with CAR T cells in the field of autoimmune disorders. We will cover first clinical results of applying anti-CD19 and anti-B cell maturation antigen CAR T cells for B cell elimination in systemic lupus erythematosus, refractory antisynthetase syndrome and myasthenia gravis, respectively. Furthermore, in preclinical models, researchers have also developed chimeric autoantibody receptor T cells that can eliminate individual B cell clones producing specific autoantibodies, and regulatory CAR T cells that do not eliminate autoreactive immune cells but dampen their wrong activation. Finally, we will address safety and manufacturing aspects for CAR T cells and discuss mRNA technologies and automation concepts for ensuring the future availability of safe and efficient CAR T cell products.

Keywords: B-Lymphocytes; autoimmune diseases; autoimmunity.

Figure 1

Adoptive immune cell therapy using autologous chimeric antigen receptor (CAR) T cells for autoimmune diseases. (A) Elimination of autoreactive B cells can be achieved by using CAR T effector cells directed against B cell markers such as CD19 resulting in a broad depletion of B cells. (B) To tailor B cell depletion, researchers have developed precision targeting of specific pathogenic B cell subpopulations that express autoantibodies to known autoantigens on their cell surface, a technology called chimeric autoantibody receptor (CAAR) T cells. (C) An alternative strategy to elimination of autoreactive cells is to dampen their activity by CAR-modified T regulatory cells (Tregs).

Figure 2

Transient mRNA-CAR T cells for improved safety of application in autoimmune diseases. (A) Stable CAR T cells permanently expressing the CAR receptor result in long-term persistence of CAR T cells. In contrast, using mRNA-CAR T cells, a transient, short-term CAR expression can be achieved and enables the administration of multiple doses as needed. (B) Stable CAR T cells are generated by applying viral vectors for CAR gene transfer into T cells, whereas transient CAR T cells utilise mRNA encoding for the CAR gene. Long-term CAR expression, as present in stable CAR T cells, comes at the expense of safety and carries the risk of genotoxicity, long-term elimination of specific cell types, and thus undesirable side effects. A high level of safety without the risks associated with permanent genetic modification is achieved by transient CAR-T cells, but their CAR-activity is temporally restricted. CAR, chimeric antigen receptor.