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European Biopharmaceutical Review

Are We Nearly There Yet? The Ongoing Journey of CAR T Cell Therapies

In 2013, Brentjens et al published results from the first clinical trial treating five adults with relapsed B cell acute lymphoblastic leukaemia (B-ALL) with CD19-directed CAR T cells. These patients had a ‘dismal’ prognosis, but all five achieved rapid tumour eradication and complete molecular remission posttreatment (1). 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 2021.

Generational Improvements in CAR T Design

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. These early CAR T cells showed promise in vitro, but in vivo displayed insufficient persistence and tumour killing activity (2). 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, which is required for full T cell activation, and, therefore, improves CAR T cell expansion, cell killing activity, and persistence (3). Fourth-generation CAR Ts aim for even greater improvements by further engineering CAR T cells to release pro-inflammatory cytokines, for example, 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 (3).

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Dr Sophie Lutter is Scientific Communications and Marketing Manager at OXGENE, a WuXi Advanced Therapies company. Sophie moved into science communication following a PhD in Developmental Biology from the Cancer Research UK London Research Institute (now part of The Francis Crick Institute), and has eight years of science communications experience within both the charity sector and biotechnology industry.
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