Chimeric antigen receptor T cell therapy: a new emerging landscape in autoimmune rheumatic diseases

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy, an innovative immune cell therapy, has revolutionized the treatment landscape of haematological malignancies. The past 2 years has witnessed the successful application of CD19-targeting CAR constructs in refractory cases of autoimmune rheumatic diseases, including systemic lupus erythematosus, systemic sclerosis and anti-synthetase syndrome. In comparison with existing B cell depletion therapies, targeting CD19 has demonstrated a more rapid and profound therapeutic effect, enabling drug-free remission with manageable adverse events. These promising results necessitate validation through long-term, large-sample randomized controlled studies. Corroborating the role of CAR-T therapy in refractory rheumatological disorders and affirming safety, efficacy and durability of responses are the aims of future clinical studies. Optimizing the engineering strategies and better patient selection are also critical to further refining the successful clinical implementation of CAR-T therapy.

Keywords: CAR-T; autoimmune rheumatic diseases; immunotherapy; lupus; myositis; scleroderma.

Figure 1.

History of chimeric antigen receptor (CAR) immune cell therapy. First constructed around early 1990s, CAR has gone through several iterations. CAR-T therapy was originally designed to target and kill tumour cells. In 2017, the first CD19-targeted CAR-T product was approved in haematological malignancy. The first case of refractory SLE successfully treated with CD19-targeted CAR-T therapy was reported in 2021, after which case reports of CAR-T therapy in autoimmune rheumatic diseases have continued to emerge. ASyS: anti-synthetase syndrome; CAR-T: chimeric antigen receptor T cell; FDA: US Food and Drug Administration. (Image created with BioRender.com)

Figure 2.

Procedure for chimeric antigen receptor (CAR)-based immune cell therapy. The original cell source can be either autologous (derived from circulating immune cells) or allogeneic (which can also be umbilical cord blood-derived). Although only CAR T cells have been reported in autoimmune rheumatic diseases, engineered Treg cells, NK cells or macrophages are promising as well. CAR genes can be intergrated into target cells through virus transduction and gene editing. The prototypic CAR contains the following parts: an antigen-binding domain, usually scFv, but it can also be designed as an antibody-receptor; a hinge and transmembrane domain; and intracellular signalling domains, usually consisting of different co-stimulatory domains and CD3ζ. After ex vivo amplification, CAR immune cells generated by the autologous route can be reinfused into the same patient. In the allogeneic route, CAR immune cells should be filtered to remove the TCR positive cells and stored. In most cases currently, the patient must be pretreated with lymphodepletion conditioning. (Image created with BioRender.com)