CD19 CAR-T cells

CAR-T is the acronym for "chimeric antigen receptor T cells". These are tumor-specific T lymphocytes with an artificial (chimeric) antigen receptor (ACAR) consisting of a single-chain variable antibody fragment (chimeric Antigen Receptor T Cells). Artificial (chimeric) antigen receptors are fusion proteins of a single-chain fragment variable of a specific monoclonal antibody and one or more intracellular T cell receptor signaling domains. This genetic modification of T cells can occur either via virus-based gene transfer methods or non-viral methods such as DNA-based transposons, CRISPR/Cas9 technology, or direct transfer of in vitro transcribed mRNA by electroporation (Miliotou AN et al. 2018).

Most CARs consist of an antigen-binding domain, an extracellular spacer/joint region, a transmembrane domain, and an intracellular signaling domain that leads to T-cell activation after antigen binding (Curran KJ et al 2012).

Lymphocytes modified in this way recognize the tumor antigen directly, without the involvement of the major histocompatibility complex (Mohanty R et al. 2019). There is now the possibility of expressing receptors against more than one antigen (bi-, tri-, quad-specific CARs). Current technologies are working to make such CART-T cells even more efficient through built-in and combinable logical "gates" ("AND", "OR", "NOT"). Thus, a CAR-T treatment combines the features of three innovative therapies - immune, cell and gene therapy.

CD19 is a member of the immunoglobulin superfamily of proteins expressed on the surface of B cells at most stages of their development, where they function as a critical component of the B cell receptor-signaling complex (Depoil D et al. 2008). CD19 is an ideal target for CAR-targeted therapies because it is expressed on most malignant B cells (including CLL, B-ALL, and many NHL), is not expressed on hematopoietic stem cells, and elimination of all CD19+ B cells in the body is a manageable on-target treatment effect (Scheuermann RH et al.1995).

A potential disadvantage of CD19 as a target is that its surface expression is not required for maintenance of the tumorigenic phenotype, and escape variants have been noted (Maude SL et al. 2014; Evans AG et al. 2015). Although not the first to be studied, CAR T-cell therapies directed against CD19 are the most mature to date (Kochenderfer JN et al. 2009). Second-generation CAR with are selected CD3ζ- and 4-1BB-stimulating domains, which is produced with a lentiviral transduction system .

Indications for anti-CD19 CAR T-cell therapy are B-cell non-Hodgkin lymphomas (Abramson JS 2020).

It is well known that autoreactive B cells play a key role in the development of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies such as rituximab have low therapeutic efficacy in autoimmune diseases (persistence of autoreactive B cells in lymphoid organs and inflamed tissues?). CD19 CAR-T cells have been introduced into autoimmune disease therapy in recent years. CD19 CAR-T cells resulted in rapid and sustained depletion of circulating B cells and complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis (Carney EF 2022; Kambayana G et al. 2023; Schett G et al. 2023).

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