Research ArticleCancer

CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors

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Science Translational Medicine  11 Jul 2018:
Vol. 10, Issue 449, eaao3240
DOI: 10.1126/scitranslmed.aao3240

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Cellular double agents

Tumor cells exhibit a “self-homing” behavior, whereby cells released into the circulation can home back to the main tumor site. To take advantage of this behavior and use the cells as vehicles to deliver therapies to the main tumor site, Reinshagen et al. engineered self-targeting tumor cells. These cells were designed to secrete death receptor–targeting ligands to which they were resistant to kill the main tumor but not destroy themselves. Conversely, they could be eliminated on demand using a drug-triggered cellular suicide system to prevent them from repopulating the tumor site. The authors then tested the efficacy and safety of this method in mouse models of primary, recurrent, and metastatic tumors.

Abstract

Tumor cells engineered to express therapeutic agents have shown promise to treat cancer. However, their potential to target cell surface receptors specific to the tumor site and their posttreatment fate have not been explored. We created therapeutic tumor cells expressing ligands specific to primary and recurrent tumor sites (receptor self-targeted tumor cells) and extensively characterized two different approaches using (i) therapy-resistant cancer cells, engineered with secretable death receptor–targeting ligands for “off-the-shelf” therapy in primary tumor settings, and (ii) therapy-sensitive cancer cells, which were CRISPR-engineered to knock out therapy-specific cell surface receptors before engineering with receptor self-targeted ligands and reapplied in autologous models of recurrent or metastatic disease. We show that both approaches allow high expression of targeted ligands that induce tumor cell killing and translate into marked survival benefits in mouse models of multiple cancer types. Safe elimination of therapeutic cancer cells after treatment was achieved by co-engineering with a prodrug-converting suicide system, which also allowed for real-time in vivo positron emission tomography imaging of therapeutic tumor cell fate. This study demonstrates self-tumor tropism of engineered cancer cells and their therapeutic potential when engineered with receptor self-targeted molecules, and it establishes a roadmap toward a safe clinical translation for different cancer types in primary, recurrent, and metastatic settings.

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