Engineered immune cells are an exciting therapeutic modality, which survey and attack
tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat
tumors and their immune-suppressive environments. Here, a new platform for arming cell
therapeutics through dual receptor and polymeric
prodrug engineering is developed. Macrophage and T cell
therapeutics are engineered to express a bioorthogonal
single chain variable fragment receptor. The receptor binds a
fluorescein ligand that directs cell loading with
ligand-tagged polymeric
prodrugs, termed "drugamers." The
fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate
prodrug monomers of the phosphoinositide-3-kinase inhibitor,
PI-103. The extended release of
PI-103 from the drugamer sustains antiproliferative activity against a
glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second
fluorescein-drugamer. This drugamer incorporates a small molecule
estrogen analog, CMP8, which stabilizes a degron-tagged transgene to provide temporal regulation of
protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene-activating small molecule
prodrugs.