DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

Xiao Huang; Jasper Z. Williams; Ryan Chang; Zhongbo Li; Eric Gai; David M. Patterson; Yu Wei; Wendell A. Lim; Tejal A. Desai

We and other groups have developed strategies to engineer T cells with multiple receptors to detect combinations of antigens [27] [28] [29] . All prior combinatorial antigen recognition systems have targeted combinations of antigens expressed on tumor cells and/or tumor-related cells 27, 29 . Here, we demonstrate a method to engineer T cells to recognize combinations of endogenous and orthogonal antigens presented by tumor cells and biocompatible materials, respectively. By incorporating material-presented antigen into combinatorial recognition circuits, we enable real-time controlled local activation of these circuits that can be achieved through dynamic particle dosing in living organisms/patients. Local injection of our particles serves to safely control receptor activation and downstream behavior of therapeutic cells in vivo. We demonstrated that synNotch-based combinatorial antigen recognition circuits can incorporate material-presented antigen sensing, and it is likely that other combinatorial antigen recognition systems, for example, chimeric costimulatory receptors (CCRs) 49 in AND-gates or inhibitory CARs (iCARs) 50 in NOT-gates, can as well.