Chimeric antigen receptor T cells also known as CAR T cells are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy.

Chimeric antigen receptors CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor.

CAR-T cell therapy uses T cells engineered with CARs for cancer therapy. The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them. Scientists harvest T cells from people, genetically alter them and then infuse the resulting CAR-T cells into patients to attack their tumours. CAR T-cells can be both CD4+ and CD8+, with a 1-to-1 ratio of both cell types providing synergistic antitumor effects.

CAR-T cells can be either derived from T cells in a patient's own blood (autologous) or derived from the T cells of another healthy donor (allogeneic). Once isolated from a person, these T cells are genetically engineered to express a specific CAR, which programs them to target an antigen that is present on the surface of tumours. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumour that is not expressed on healthy cells.

After CAR-T cells are infused into a patient, they act as a "living drug" against cancer cells. When they come in contact with their targeted antigen on a cell, CAR-T cells bind to it and become activated, then proceed to proliferate and become cytotoxic. CAR-T cells destroy cells through several mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the increased secretion of factors that can affect other cells such as cytokines, interleukins and growth factors. The first CAR-T cell therapies were FDA-approved in 2017, and there are now 5 approved CAR-T therapies.

Clinical applications                                                                                                             

As of March 2019, there were around 364 on-going clinical trials happening globally involving CAR-T cells. The majority of those trials target blood cancers: CAR-T therapies account for more than half of all trials for hematological malignancies. CD19 continues to be the most popular antigen target, followed by BCMA (commonly expressed in multiple myeloma). In 2016, studies began to explore the viability of other antigens, such as CD20. Trials for solid tumours are less dominated by CAR-T, with about half of cell therapy-based trials involving other platforms such as NK cells.

Cancer

T cells are genetically engineered to express chimeric antigen receptors specifically directed toward antigens on a patient's tumour cells, they are then infused into the patient where they attack and kill the cancer cells. Adoptive transfer of T cells expressing CARs is a promising anti-cancer therapeutic, because CAR-modified T cells can be engineered to target virtually any tumour associated antigen.

Early CAR-T cell research has focused on blood cancers. The first approved treatments use CARs that target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). There are also efforts underway to engineer CARs targeting many other blood cancer antigens, including CD30 in refractory Hodgkin's lymphoma; CD33, CD123, and FLT3 in acute myeloid leukemia (AML) and BCMA in multiple myeloma.

Solid tumours have presented a more difficult target. Identification of good antigens has been challenging: such antigens must be highly expressed on the majority of cancer cells, but largely absent on normal tissues. CAR-T cells are also not trafficked efficiently into the center of solid tumor masses, and the hostile tumour microenvironment suppresses T cell activity.

Autoimmune disease

While most CAR T-cell studies focus on creating a CAR T-cell that can eradicate a certain cell population there are other potential uses for this technology. T-cells can also protect self-antigens from autoimmune reactions. A regulatory T-cell outfitted with a CAR could have the potential to confer tolerance to a specific antigen, something that could be utilized in organ transplantation or rheumatic diseases like lupus.

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Immunotherapy: Open Access

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