Programmable Chimeric Antigen Receptor T Cell Circuits With DNA Computing for Precision Tumor Therapy.

Chimeric antigen receptor (CAR) T cells, a promising cancer therapeutics, still face challenges in safety and efficacy due to the incapability to precisely regulate T cell activation. Here we develop a DNA-logic CAR (DL-CAR) system that enables programmable targeting and precise ablation of tumors with specific antigen combination patterns. The DL-CAR system is engineered using HaloTag as an extracellular domain for DNA conjugation, which allows controlling the assembly of tumor-targeting aptamers for universal and combinatorial antigen recognition via DNA logic computation. DL-CAR-T cells are shown to be capable of targeting tumor cells with different antigens and controlling the CAR circuit through AND, OR, and INHIBIT Boolean logic for specific T-cell activation and cytolysis. The DL-CAR system demonstrated high efficacy for tumor eradication in mouse models, with the AND-, OR-, and INHIBIT-gated computation affording enhanced selectivity for tumors with specific antigen combinations. DL-CAR may provide a new paradigm to develop programmable CAR-T circuits for precision cancer therapy.