Chimeric Antigen Receptor T-cell therapy in systemic autoimmune rheumatic diseases: current insights and future prospects

Abstract

Chimeric Antigen Receptor (CAR) T-cell therapy, revolutionary in treating hematological malignancies, is emerging as a promising approach for systemic autoimmune rheumatic diseases (SARDs). This review examines the potential of CAR T-cell therapy in treating conditions such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myopathies (IIMs). The evolution of CAR T cells technology, from first to fifth generation, has enhanced its efficacy and persistence. Early clinical studies in SARDs have shown encouraging results, with some patients achieving drug-free remission. CD19-targeted CAR T cells have demonstrated significant B-cell depletion and clinical improvement in patients with SLE, SSc, and IIMs. Despite promising outcomes, challenges remain, including cytokine release syndrome and the need for careful patient selection. Future directions include exploring dual-targeting CARs, chimeric autoantibody receptors (CAARs), and alternative cell sources like γδ T cells, regulatory T cells, natural killer cells. The integration of CAR-based cell therapy into treatment paradigms of patients with SARDs requires further research to optimize efficacy, mitigate side effects, and identify suitable target biomarkers. While hurdles exist CAR-based cell therapy holds the potential to revolutionize management of patients with SARDs, offering hope for long-term, drug-free remission in these complex autoimmune conditions.

Keywords: Autoimmune diseases; Chimeric Antigen Receptor T-cell therapy; Idiopathic inflammatory myopathy; Systemic lupus erythematosus; Systemic sclerosis.

Figure 1

Overview of Chimeric Antigen Receptor (CAR) T cells production and mechanism of action. A schematic illustration depicting the key steps in CAR T-cell therapy process and the structure of a CAR. The left figure shows the basic structure of a CAR, consisting of an extracellular domain with variable heavy (VH) and light (VL) chains, a hinge region, a transmembrane domain, and an intracellular signaling domain. The numbered steps illustrate the production and administration process: (1) Leukapheresis is performed to collect the patient’s T cells. (2) The collected T cells are genetically modified using viral vectors to express the CAR. (3) The engineered T cells expressing CAR undergo selection. (4) Selected CAR T cells are expanded ex vivo to achieve therapeutic numbers. (5) The expanded CAR T cells are formulated for infusion. (6) After administration, CAR T cells recognize and eliminate target cells expressing specific antigens. This process has shown promising results in treating various systemic autoimmune rheumatic diseases. Adapted from the article of Guffroy et al. (Joint Bone Spine 2024;91:105702) [14].

Figure 2

The evolution of Chimeric Antigen Receptor (CAR) technology for systemic autoimmune rheumatic diseases (SARDs). This figure illustrates the evolution of CAR technology from its inception in the 1980s to future directions. Early CARs in the 1980~1990s featured a basic design with a CD3ζ signaling domain but limited efficacy. The 2000s saw the introduction of second-generation CARs with costimulatory domains (e.g., CD28 or 4-1BB) to enhance T-cell activation, and third-generation CARs combined multiple costimulatory domains for improved antitumor activity. In the 2010s, fourth-generation CARs incorporated transcriptional activation domains like NFAT to induce cytokine release (e.g., IL-12 or IL-18), while fifth-generation CARs added cytokine receptor signaling pathways (e.g., IL-2Rβ and JAK-STAT) for enhanced functionality. The 2020s brought advanced CAR variants such as CAAR-T cells for pathological B-cell depletion, dual-targeting CARs, CAR-γδ T cells, CAR-NK cells, allogeneic CAR T cells derived from stem cells. Looking ahead, CAR technologies are being explored for SARDs like systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and idiopathic inflammatory myopathy (IIM), with innovations targeting diverse immune subsets and enhancing therapeutic efficacy while reducing toxicity. CD: cluster of differentiation, IL: interleukin, JAK: Janus kinase, STAT: signal transducer and activator of transcription, NK cells: natural killer cells, NMDAR: N-methyl-D-aspartate receptor, BCMA, B-cell maturation antigen, NFAT: nuclear factor of activated T cells, TCR: T-cell receptor, CAAR: chimeric autoantibody receptor.

Figure 3

Fundamental principles and new approaches of Chimeric Antigen Receptor (CAR)-based cell therapy. The figure illustrates the two main approaches to CAR-based cell therapy: autologous and allogeneic. In autologous therapy, immune cells are collected from the patient, while allogeneic therapy utilizes cells from healthy donors. Various immune cell types can be engineered to express CARs, including conventional T cells, regulatory T cells (T Reg cells), natural killer (NK) cells, and macrophages. Before CAR-cell infusion, patients typically undergo lymphodepletion pretreatment to create a favorable environment for the engineered cells. This comprehensive diagram showcases the versatility of CAR-based therapy platforms and their potential applications in treating systemic autoimmune rheumatic diseases (SARDs). The ability to utilize different cell types and sources provides multiple therapeutic strategies that can be tailored to individual patient needs. Adapted from the article of Capsomidis et al. (Mol Ther 2018;26:354-65) [67], Doglio et al. (Nat Commun 2024;15:2542) [68], Hassan et al. (Med Oncol 2024;41:127) [69], Aparicio et al. (Exp Hematol Oncol 2023;12:73) [70], and Sadeqi Nezhad et al. (Pharm Res 2021;38:931-45) [71].