Kaitlyn Pierpont

Cytotoxic chemotherapies have low therapeutic indices, resulting in systemic toxicities that limit their overall efficacy. Prodrug formulations reduce cytotoxicity in healthy tissues but require a tumor-specific stimulus to release their parent drugs. Antibody-based delivery of bacterial enzymes has been explored as a pre-targeting method to selectively activate prodrugs at the tumor site. However, these attempts have faced challenges including insufficient enzyme accumulation and induction of humoral immune responses. We propose a chimeric antigen receptor (CAR) T cell-based delivery approach, in which CAR T cells are engineered to secrete human peptide deformylase (HsPDF) as they proliferate at the tumor site. Endogenous HsPDF is confined within mitochondria, making it minimally accessible to administered HsPDF-cleavable prodrugs. Delivery of HsPDF to the tumor site by CAR T cells enables localized activation of prodrugs and synergistic tumor killing while reducing immunogenicity.