Abstract
Targeted radionuclide therapy (TRT) is an emerging therapeutic modality for the treatment of various solid cancers. Current approaches rely on the presence of cancer-specific epitopes and receptors against which a radiolabeled ligand is systemically administered to specifically deliver cytotoxic doses of α and β particles to tumors. In this proof-of-concept study, tumor-colonizing Escherichia coli Nissle 1917 (EcN) is utilized to deliver a bacteria-specific radiopharmaceutical to solid tumors in a cancer-epitope independent manner. In this microbe-based pretargeted approach, the siderophore-mediated metal uptake pathway is leveraged to selectively concentrate copper radioisotopes, 64 Cu and 67 Cu, complexed to yersiniabactin (YbT) in the genetically modified bacteria. 64 Cu-YbT facilitates positron emission tomography (PET) imaging of the intratumoral bacteria, whereas 67 Cu-YbT delivers a cytotoxic dose to the surrounding cancer cells. PET imaging with 64 Cu-YbT reveals persistence and sustained growth of the bioengineered microbes in the tumor microenvironment. Survival studies with 67 Cu-YbT reveals significant attenuation of tumor growth and extends survival of both MC38 and 4T1 tumor-bearing mice harboring the microbes. Tumor response to this pretargeted approach correlates with promising anti-tumor immunity, with noticeable CD8+ T:Treg cell ratio. Their strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype.