Figure 3.

Targeting CD28 to optimize co-stimulatory signals. (A), (B). Site-directed mutagenesis of amino acid residues in the CD28 domain abrogate binding of adaptor signaling molecules. (C). Genetic deletion of the endogenous CD28 receptor eliminates additional co-stimulatory signals delivered to CAR-T cells in vivo. Reductions in CD28-mediated activation signals preserve stem memory/central memory phenotypes, reduce expression and chromatin accessibility of exhaustion-associated genes and promote enhanced CAR-T cell persistence in preclinical models [72,73,74].