CAR-T cells have a genetically engineered T-cell receptor (TCR) that directs their binding to cancer cells. In first-generation CARs, the TCR was engineered to express a new, antigen-binding domain, usually the single-chain variable fragment (scFv) of an antibody. Sophie Lutter at Oxgene discusses more about the ongoing journey of CART-T cell therapies.
‘Are We Nearly There Yet? The Ongoing Journey of CAR-T Cell Therapies’
Brentjens et al. published results from the first clinical trial treating five adults with relapsed B call acute lymphoblastic leukemia (B-ALL) with CD19-directed CART-T calls in 2013. These patients has a “dismal” prognosis, but all five achieved rapid tumour eradication and complete molecular remission post treatment. These remarkable results set the stage for a flurry of CAR-T research and clinical trials culminating in FDA approvals of two CAR-T therapies, Kymriah (Novartis) and Yescarta (Kite Pharma), in 2017. These approvals were followed by Tecartus (Kite Pharma) in 2020, and Breyanzi and Abecma (both Bristol Myers Squibb) in 2011.
Generational Improvements in CAR-T Design
CAR-T calls have a genetically engineered T-cell receptor (TCR) that directs their binding to cancer cells. In first generation CARs and TCR was engineered to express a new, antigen binding domain, usually the single chain variable fragment (scFv) of an antibody. These early CAR-T cells showed promise in vitro, but in vivo displayed insufficient persistence and tumour killing activity. Second and third generation CAR-T cells addressed this by incorporating one or two co-stimulatory domains respectively into a first-generation CAR-t backbone. This mimics the co-stimulation normally provided by antigen presenting cells (APC), which is required for full T-cell activation, and therefore improves CAR-T cell expansion, cell-killing activity and persistence. Fourth generation CAR-T’s aim for even greater improvements by further engineering CAR-T cells to release pro-inflammatory cytokines, like Interleukin-2 (IL-2), into the tumour microenvironment. This stimulates the innate immune system to divert endogenous immune cells towards the tumour, further enhancing tumour killing activity.
The latter strategy is particularly advantageous, because it raises the possibility of an effective anticancer immune response even in the absence of universal expression of the target antigen on cancer cells, which is important since many cancers rely on antigen heterogeneity and spontaneous downregulation to evade the immune response.
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