Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2223 - 2228
• Main Authors: Dondossola, Eleonora, Dobroff, Andrey S., Marchiò, Serena, Cardó-Vila, Marina, Hosoya, Hitomi, Libutti, Steven K., Corti, Angelo, Sidman, Richard L., Arap, Wadih, Pasqualini, Renata
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-02-2016; National Acad Sciences
• Subjects: Animals; Apoptosis; Biological Sciences; Carcinoma, Lewis Lung - pathology; Carcinoma, Lewis Lung - secondary; Carcinoma, Lewis Lung - therapy; Cell Engineering; Cell Line, Tumor; Cell- and Tissue-Based Therapy; Cytokines; Drug Delivery Systems; Endothelium, Vascular - pathology; Female; Genetic engineering; Humans; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - secondary; Mammary Neoplasms, Experimental - therapy; Melanoma, Experimental - pathology; Melanoma, Experimental - secondary; Melanoma, Experimental - therapy; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms, Experimental - pathology; Neoplasms, Experimental - secondary; Neoplasms, Experimental - therapy; Oncology; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Recombinant Proteins - therapeutic use; Rodents; Transduction, Genetic; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - therapeutic use; Tumor necrosis factor-TNF; Tumors; Xenograft Model Antitumor Assays; apoptosis; endothelial cells; vascular damaging agent; tumor necrosis factor; engineered tumor cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1525697113

Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed “tumor self-seeding.” Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as “tumor self-targeting.” For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell–mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.