CAR (Chimeric Antigen Receptor) T cells are T cells that have been engineered with additional receptors to identify specific proteins, called antigens, present on the surface of other cells. CAR-enabled targeting is the basis of numerous immuno-oncology treatments across the biotechnology industry, where CAR T cell therapy has shown remarkable clinical success.
Most CARs have a similar structure that includes an extracellular target binding domain derived from antibodies and an intracellular signaling domain derived from the natural T cell receptor complex. The extracellular domain is typically a single-chain variable fragment (scFv) that binds specifically to a target antigen on cancer cells, such as CD19. The intracellular domain most commonly incorporates CD3 Zeta, a primary component of the natural T cell receptor that triggers the release of cytotoxins, which kill the target cell. More recent CARs include additional costimulatory domains, such as 4-1BB (CD137), to increase the engineered cells’ cytokine production and self-replication for a more durable and potent clinical result.
Two CD19-specific CAR T cell products, Kymriah® and Yescarta®, achieved regulatory approval in 2017 for types of cancers, including acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL). While these products provide deep and durable responses for many patients with certain B cell-related cancers, their design results in the complete elimination of cancerous as well as all normal protective B cell populations, which can be associated with well-described side effects.
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