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Engineering potent chimeric antigen receptor T cells by programming signaling during T-cell activation. | LitMetric

AI Article Synopsis

  • Researchers at Lyell Immunopharma developed Stim-R technology, a synthetic biomimetic that enhances T-cell activation for better therapeutic outcomes.
  • Different formulations of Stim-R were tested, leading to an optimized version that created more effective ROR1-targeted CAR T cells with improved durability and functionality compared to standard methods.
  • Analysis showed that these CAR T cells had a reduced risk of exhaustion and maintained a specific subset of stem-like cells, resulting in superior tumor control in solid tumor models.

Article Abstract

Programming cell signaling during T-cell activation represents a simple strategy for improving the potency of therapeutic T-cell products. Stim-R technology (Lyell Immunopharma) is a customizable, degradable synthetic cell biomimetic that emulates physiologic, cell-like presentation of signal molecules to control T-cell activation. A breadth of Stim-R formulations with different anti-CD3/anti-CD28 (αCD3/αCD28) antibody densities and stoichiometries were screened for their effects on multiple metrics of T-cell function. We identified an optimized formulation that produced receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeted chimeric antigen receptor (CAR) T cells with enhanced persistence and polyfunctionality in vitro, as assessed in repeat-stimulation assays, compared with a benchmark product generated using a conventional T-cell-activating reagent. In transcriptomic analyses, CAR T cells activated with Stim-R technology showed downregulation of exhaustion-associated gene sets and retained a unique subset of stem-like cells with effector-associated gene signatures following repeated exposure to tumor cells. Compared with the benchmark product, CAR T cells activated using the optimized Stim-R technology formulation exhibited higher peak expansion, prolonged persistence, and improved tumor control in a solid tumor xenograft model. Enhancing T-cell products with Stim-R technology during T-cell activation may help improve therapeutic efficacy against solid tumors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392953PMC
http://dx.doi.org/10.1038/s41598-024-72392-1DOI Listing

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