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

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:T_reg cell ratio. Their strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype.