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

Area of Science:

• Immunology
• Biotechnology
• Cell Therapy

Background:

• Optimizing T-cell activation is crucial for enhancing the efficacy of T-cell-based immunotherapies.
• Current methods for T-cell activation may not fully leverage the potential of therapeutic T cells.

Purpose of the Study:

• To evaluate Stim-R technology, a synthetic biomimetic, for programming T-cell activation.
• To determine if optimized Stim-R formulations can improve the function and therapeutic potential of chimeric antigen receptor (CAR) T cells.

Main Methods:

• Screening of various Stim-R formulations with different anti-CD3/anti-CD28 antibody densities and stoichiometries.
• Assessing T-cell function using repeat-stimulation assays and transcriptomic analyses.
• Evaluating ROR1-targeted CAR T-cell efficacy in a solid tumor xenograft model.

Main Results:

• An optimized Stim-R formulation enhanced in vitro persistence and polyfunctionality of CAR T cells compared to a benchmark.
• Transcriptomic analysis revealed reduced exhaustion markers and a preserved stem-like cell population in Stim-R activated CAR T cells.
• Stim-R activated CAR T cells demonstrated improved tumor control in vivo.

Conclusions:

• Stim-R technology offers a novel approach to program T-cell activation for improved therapeutic outcomes.
• Optimized Stim-R formulations can enhance CAR T-cell potency, persistence, and anti-tumor activity, particularly against solid tumors.