Editors' ChoiceCancer Immunotherapy

TRAIL-Blazing Therapy Against Circulating Tumor Cells

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Science Translational Medicine  29 Jan 2014:
Vol. 6, Issue 221, pp. 221ec18
DOI: 10.1126/scitranslmed.3008472

Although circulating tumor cells (CTCs) are a rare population in blood, they pose a major threat in the formation of metastatic tumor sites. There have been major advances in the detection of CTCs that should improve diagnosis and tracking of cancer progression; however, approaches to treating CTCs have continued to lag. Mitchell and colleagues demonstrate one potential method of treating CTCs through the targeted functionalization of circulating leukocytes with tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL). This therapy can serve to target and kill rare tumor populations that contribute to cancer metastasis, a leading cause of cancer-related death.

Because both CTCs and leukocytes can bind E-selectin (ES), ES/TRAIL-conjugated nanoparticle-sized liposomes were used to deliver TRAIL to both cell types. Whereas ES/TRAIL liposomes alone could induce apoptosis in cancer cells under shear flow in buffer, apoptosis was enhanced in human blood through the functionalization of leukocytes with TRAIL. Interestingly, neither leukocytes nor endothelial cells exhibited detectable toxicity from ES/TRAIL liposome treatment. In contrast, cancer cells were potently affected by functionalized leukocytes presenting TRAIL in vitro when spiked into human blood. This effect was further confirmed in vivo, when mice were treated with ES/TRAIL liposomes after intravenous injection of human cancer cells. ES/TRAIL-treated mice had more than 65-fold reduction in CTC blood concentration and a reduction in tumor cells lodged in the lung. Analysis of the tumor cells found in the mouse lungs revealed an increase in apoptosis in ES/TRAIL-treated mice as compared with controls.

This work suggests that functionalization of leukocytes may be an effective method for treatment of CTCs. Some questions remain as to how easily this approach will translate into the clinic, because multiple components are required for targeted functionalization of leukocytes by liposomes. Furthermore, more work remains to understand why leukocytes are not affected by TRAIL when given TRAIL in this manner. Beyond TRAIL, however, the work should encourage the evaluation of other insightful approaches for functionalizing leukocytes against CTCs.

M. J. Mitchell et al., TRAIL-coated leukocytes that kill cancer cells in the circulation. Proc. Natl. Acad. Sci. U.S.A. 111, 930–935 (2014). [Abstract]

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