CD19 CAR-T cell therapy: a new dawn for autoimmune rheumatic diseases?

Abstract

Autoimmune rheumatic diseases (ARDs), such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, involve dysregulated immune responses causing chronic inflammation and tissue damage. Despite advancements in clinical management, many patients do not respond to current treatments, which often show limited efficacy due to the persistence of autoreactive B cells. Chimeric antigen receptor (CAR)-T cell therapy, which has shown success in oncology for B cell malignancies, targets specific antigens and involves the adoptive transfer of genetically engineered T cells. CD19 CAR-T cells, in particular, have shown promise in depleting circulating B cells and achieving clinical remission. This review discusses the potential of CD19 CAR-T cells in ARDs, highlighting clinical achievements and addressing key considerations such as optimal target cell populations, CAR construct design, acceptable toxicities, and the potential for lasting immune reset, crucial for the safe and effective adoption of CAR-T cell therapy in autoimmune treatments.

Keywords: CD19 CAR-T; autoimmune rheumatic diseases; rheumatoid arthritis; systemic lupus erythematosus; systemic sclerosis.

Figure 1

CAR-T manufacturing process. First, cells from the patient’s immune system are collected by leukapheresis. Then, T cells are separated from other blood components and undergo a gene transfer process, usually using a viral vector. This results in the expression of chimeric antigen receptors (CARs) on the surface of the T cells. After ex vivo amplification of the modified T cells, and after batch validation, this product re-infused into the same patient. Prior to infusion, patients normally undergo lymphocyte depletion conditioning chemotherapy. (Figure created with www.biorender.com).

Figure 2

Overview of CAR-T development from TCR. (Left) T cell receptor (TCR) is a natural complex formed by six chains: two variable chains (α and β) that bind specific antigens after MHC-II presentation and four constant chains (γ, 𝛿, ϵ and 𝜁) that activate the T cell after 1^st signal. Second co-stimulation signal, normally from CD28, is necessary for maintaining activation. (Right) On the other hand, chimeric antigen receptor (CAR) is an artificial receptor with three domains: one that recognizes antigens independently of the HLA complex (scFv, single chain variable fragment) and is linked by a transmembrane domain to the activation domain CD3𝜁 to activate the T cell in the first generation of CAR. Second and third generation includes one and two more costimulatory domains (CM1 and CM2), respectively. Most frequent CM encloses CD28 or 4-1BB. Forth CAR generation also express bioactive molecules such as cytokines or Bi-specific T-cell engagers (BiTEs). General levels of activation or potency are represented with a star symbol: yellow star indicates the potential to modulate microenvironment (figure created with www.biorender.com).

Figure 3

CAR-T strategies for autoimmune diseases. Classic CAR-T strategies genetically modified CD4/CD8 T cells for expressing CD19 and target healthy and autoreactive B cells, thus releasing perforin and granzyme to induce cell death. CAAR-T cells are a version of classic CAR-T cells, that expresses a Chimeric Autoantibody Receptor (CAAR) directed exclusively to autoreactive B cell clones. Third strategy modified T regulatory or T cells to express FoxP3+ and to modulate the autoreactive response. SLE: Systemic Lupus Erythematosus; SSc: Systemic Sclerosis; RA: Rheumatoid Arthritis; ANCA-associated vasculitis: Anti-Neutrophil Cytoplasmic Antibody associated vasculitis. (Figure created with www.biorender.com).