An Engineered Probiotic Platform for Cancer Epitope-independent Targeted Radionuclide Therapy of Solid Tumors.

Targeted radionuclide therapy is an emerging therapeutic modality for the treatment of various forms of 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, we utilized tumor-colonizing Escherichia coli Nissle 1917 to deliver a bacteria-specific radiopharmaceutical to solid tumors in a cancer-epitope independent manner. In this microbe-based pretargeted approach, we leveraged the siderophore-mediated metal uptake pathway to selectively concentrate copper radioisotopes, 64 Cu and 67 Cu, complexed to yersiniabactin in our genetically modified probiotic bacteria. In this modular and switchable platform, 64 Cu-yersiniabactin facilitated PET/CT imaging of the intratumoral bacteria, whereas 67 Cu-yersiniabactin delivered a cytotoxic dose to the surrounding cancer cells. PET/CT imaging with 64 Cu-yersiniabactin revealed persistence and sustained growth of our bioengineered microbes in the tumor microenvironment. Survival studies with 67 Cu-yersiniabactin revealed significant attenuation of tumor growth and extended survival of both MC38 and 4T1 syngeneic tumor-bearing mice harboring the microbes, compared to control groups. Tumor response to this pretargeted approach correlated with promising anti-tumor immunity, with noticeable CD8 + T: T reg cell ratio. This radio-microbial strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype. This article is protected by copyright. All rights reserved.