DefinitionThis section has been translated automatically.
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).
Pharmacodynamics (Effect)This section has been translated automatically.
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 .
IndicationThis section has been translated automatically.
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).
LiteratureThis section has been translated automatically.
- Abramson JS (2020) Anti-CD19 CAR T-cell therapy for B-cell non-Hodgkin lymphoma. Transfus Med Rev 34:29-33.
- Carney EF (2022) Treatment of SLE with anti-CD19 CAR-T cells. Nat Rev Nephrol 18:743.
- Curran KJ et al (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med 14:405-415.
- Depoil D et al (2008) CD19 is essential for b cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol 9:63-72.
- Evans AG et al (2015) Evolution to plasmablastic lymphoma evades cd19-directed chimeric antigen receptor T cells. Br J Haematol Epub ahead of print.
- Grupp SA et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518.
- Haji-Fatahaliha M et al (2016) CAR-modified T-cell therapy for cancer: an updated review. Artif Cells Nanomed Biotechnol 44:1339-1349.
- Kambayana G et al (2023) Autologous CD19-targeted chimeric antigen receptor (CAR)T-cells as the Future of Systemic Lupus Erythematosus Treatment. Curr Rheumatol Rev 19:260-269.
- Kochenderfer JN et al (2009) Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother 32:689-702.
- Maude SL et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517.
- Miliotou AN et al (2018) CAR T-cell Therapy: A New Era in Cancer Immunotherapy. Curr Pharm Biotechnol 19: 5-18.
- Mohanty R et al (2019) CAR T cell therapy: A new era for cancer treatment (Review). Oncol Rep 42(6):2183-2195.
- Mougiakakos D et al (2021) CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med. 5;385: 567-569.
- Schett G et al (2023) CAR T-cell therapy in autoimmune diseases. Lancet: S0140-6736.
- Scheuermann RH et al (1995) CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma 18:385-397.
- Yu YD et al (2021) Chimeric Antigen Receptor-Engineered T Cell Therapy for the Management of Patients with Metastatic Prostate Cancer: A Comprehensive Review. Int J Mol Sci 22: 640.