Bridget A Kennis1, Keith A Michel2, William B Brugmann1, Alvaro Laureano1,3, Rong-Hua Tao1, Srinivas S Somanchi1, Samuel A Einstein2, Javiera B Bravo-Alegria1, Shinji Maegawa1, Andrew Wahba1, Simin Kiany1, Nancy Gordon1, Lucia Silla3, Dawid Schellingerhout4, Soumen Khatua1, Wafik Zaky1, David Sandberg1,5, Laurence Cooper1,6, Dean A Lee7,8, James A Bankson9,10, Vidya Gopalakrishnan11,12. 1. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Division of Transplantation and Cellular Therapy, Hospital das Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 4. Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Pediatric Neurosurgery, University of Texas Health Science Center, Houston, TX, USA. 6. Ziopharm Oncology, Boston, MA, USA. 7. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Dean.Lee@nationwidechildrens.org. 8. Department of Pediatrics, Ohio State University, 700 Children's Dr, Columbus, OH, 43205, USA. Dean.Lee@nationwidechildrens.org. 9. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jbankson@mdanderson.org. 10. Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1902, Houston, TX, 77030, USA. jbankson@mdanderson.org. 11. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. VGopalak@mdanderson.org. 12. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0853, Houston, TX, 77030, USA. VGopalak@mdanderson.org.
Abstract
PURPOSE: Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.
PURPOSE:Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficientmice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.
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