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Neural Progenitor Cell-mediated Delivery of Interferon Beta Improves Neuroblastoma Response to Cyclophosphamide

  • Pediatric Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

We have shown that continuous systemic delivery of interferon beta (IFN-β) remodels dysfunctional tumor vasculature, thereby improving tumor perfusion and enhancing delivery and efficacy of chemotherapeutic drugs. We hypothesized that because of their inherent tumor tropism, neural progenitor cells (NPCs) engineered to express IFN-β could also effect maturation of tumor vasculature without generating high systemic levels of IFN-β.

Methods

Mice with luciferase-expressing disseminated human neuroblastoma were divided into four groups of equal tumor burden by bioluminescence imaging: (1) untreated controls; (2) NPC-IFN-β only; (3) cyclophosphamide (CTX) only; and (4) NPC-IFN-β in combination with CTX. Two million NPC-IFN-β cells were administered twice, 7 days apart, starting 21 days after tail vein administration of tumor cells. CTX was administered every 6 days for three doses. Mice were killed at 6 weeks, livers and kidneys weighed, and tumor removed for immunohistochemical staining for endothelial cells (CD34), pericytes (α-SMA), apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick-end labeling]), and diI-labeled NPCs.

Results

Fluorescent-labeled NPCs confirmed localization of these cells to tumors. The α-SMA/CD34 ratio, a marker for vascular maturation, greatly increased in NPC-IFN-β-treated tumors compared with controls. Bioluminescent signal from luciferase-expressing tumor cells, reflecting tumor burden, was lower with combination therapy than control or either monotherapy, and combination therapy resulted in far less tumor burden by weight in the kidneys and liver.

Conclusions

Targeted delivery of IFN-β with NPCs produced low circulating levels of IFN-β, yet the maturing effect on the tumor vasculature and the enhanced efficacy of adjuvant therapy was maintained. Thus, combination therapy of NPC-IFN-β with CTX warrants further investigation for the treatment of high-risk neuroblastoma patients.

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References

  1. Miller RW, Young JL Jr, Novakovic B. Childhood cancer. Cancer 1995;75(1 Suppl):395–405

    Article  PubMed  CAS  Google Scholar 

  2. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 1999;341:1165–73

    Article  PubMed  CAS  Google Scholar 

  3. Streck CJ, Ng CY, Zhang Y, et al. Interferon-mediated anti-angiogenic therapy for neuroblastoma. Cancer Lett 2005;228:163–70

    Article  PubMed  CAS  Google Scholar 

  4. Streck CJ, Zhang Y, Miyamoto R, et al. Restriction of neuroblastoma angiogenesis and growth by interferon-alpha/beta. Surgery 2004;136:183–9

    Article  PubMed  Google Scholar 

  5. McCarville MB, Streck CJ, Dickson PV, et al. Angiogenesis inhibitors in a murine neuroblastoma model: quantitative assessment of intratumoral blood flow with contrast-enhanced gray-scale US. Radiology 2006;240:73–81

    Article  PubMed  Google Scholar 

  6. Le Serve AW, Hellmann K. Metastases and the normalization of tumour blood vessels by ICRF 159: a new type of drug action. Br Med J 1972;1(5800):597–601

    Article  PubMed  CAS  Google Scholar 

  7. Teicher BA, Holden SA, Ara G, et al. Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents. Int J Cancer 1994;57:920–5

    Article  PubMed  CAS  Google Scholar 

  8. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987–9

    Article  PubMed  CAS  Google Scholar 

  9. Dickson PV, Hamner JB, Streck CJ, et al. Continuous delivery of IFN-beta promotes sustained maturation of intratumoral vasculature. Mol Cancer Res 2007;5:531–42

    Article  PubMed  CAS  Google Scholar 

  10. Dickson PV, Hamner JB, Sims TL, et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 2007;13:3942–50

    Article  PubMed  CAS  Google Scholar 

  11. Dickson PV, Hagedorn NL, Hamner JB, et al. Interferon-β mediated improved efficacy of systemically administered topotecan in a murine neuroblastoma model. J Pediatr Surg 2007;42:160–5

    Article  PubMed  Google Scholar 

  12. Einhorn S, Grander D. Why do so many cancer patients fail to respond to interferon therapy? J Interferon Cytokine Res 2006;16:275–81

    Google Scholar 

  13. Salmon P, Le Cotonnec JY, Galazka A, et al. Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers. J Interferon Cytokine Res 1996;16:759–64

    PubMed  CAS  Google Scholar 

  14. Bendetti S, Pirola B, Pollo B, et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000;6:447–50

    Article  CAS  Google Scholar 

  15. Aboody KS, Najbauer J, Schmidt NO, et al. Targeting of melanoma brain metastases using engineered neural stem/progenitor cells. Neuro Oncol 2006;8:119–26

    Article  PubMed  CAS  Google Scholar 

  16. Brown A, Yang W, Schmidt N, et al. Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Hum Gene Ther 2003;14:1777–85

    Article  PubMed  CAS  Google Scholar 

  17. Aboody K, Brown A, Rainov N, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 2000;97:12846–51

    Article  PubMed  CAS  Google Scholar 

  18. Danks MK, Yoon KJ, Bush R, et al. Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 2007;67:22–5

    Article  PubMed  CAS  Google Scholar 

  19. Dickson PV, Hamner JB, Burger R, et al. Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-β and restricts tumor growth in a murine model of disseminated neuroblastoma. J Pediatr Surg 2007;42:48–53

    Article  PubMed  Google Scholar 

  20. Kim S, Nakagawa E, Hatori K, et al. Production of immortalized human neural crest stem cells. Methods Mol Biol 2002;198:55–65

    PubMed  Google Scholar 

  21. Dickson PV, Hamner B, Ng CY, et al. In vivo bioluminescence imaging for early detection and monitoring of disease progression in a murine model of neuroblastoma. J Pediatr Surg 2007;42:1172–9

    Article  PubMed  Google Scholar 

  22. Ory DS, Neugeboren BA, Mulligan RC. A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. Proc Natl Acad Sci U S A 1996;93:11400–6

    Article  PubMed  CAS  Google Scholar 

  23. Spurbeck WW, Ng CY, Strom TS, et al. Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. Blood 2002;100:3361–8

    Article  PubMed  CAS  Google Scholar 

  24. Tong RT, Boucher Y, Kozin SV, et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004;64:3731–6

    Article  PubMed  CAS  Google Scholar 

  25. Lo C, Liu C, Chan S, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007;24:831–42

    Article  Google Scholar 

  26. Moschos S, Kirkwood J. Present role and future potential of type I interferons in adjuvant therapy of high-risk operable melanoma. Cytokine Growth Factor Rev 2007;18:451–8

    Article  PubMed  CAS  Google Scholar 

  27. Wakabayashi T, Natsume A, Hashizume Y, et al. A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy. J Gene Med 2008;10:329–39

    Article  PubMed  CAS  Google Scholar 

  28. Tanabe T, Kominsky S, Subramaniam P, et al. Inhibition of the glioblastoma cell cycle by type I IFNs occurs at both the G1 and S phases and correlates with the upregulation of P21 (WAF1/CIP1). J Neurooncol 2000;48:225–32

    Article  PubMed  CAS  Google Scholar 

  29. Kirkwood JM, Richards T, Zarour H, et al. Immunomodulatory effects of high-dose and low-does interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of Intergroup Adjuvant Trial E1690. Cancer 2002;95:1101–12

    Article  PubMed  CAS  Google Scholar 

  30. Chen Q, Gong B, Mahmoud-Ahmed A, et al. Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma. Blood 2001;98:2183–92

    Article  PubMed  CAS  Google Scholar 

  31. Slaton JW, Perrotte P, Inoue K, et al. Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin Cancer Res 1999;5:2726–34

    PubMed  CAS  Google Scholar 

  32. Hori J, Ng TF, Shatos M, et al. Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 2003;21:405–16

    Article  PubMed  Google Scholar 

  33. Odeberg J, Piao JH, Samuelsson EB, et al. Low immunogenicity of in vitro–expanded human neural cells despite high MHC expression. J Neuroimmunol 2005;161:1–11

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by the Assisi Foundation of Memphis, the U.S. Public Health Service Childhood Solid Tumor Program Project (grant CA23099), the Cancer Center Support Grant (grant 21765) from the National Cancer Institute, and the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Surgery, University of Tennessee Health Science Center, 920 Madison Avenue, Memphis, TN, 38163, USA

    Thomas L. Sims Jr. MD, John B. Hamner MD, Regan F. Williams MD & Andrew M. Davidoff MD

  2. Department of Surgery, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Thomas L. Sims Jr. MD, John B. Hamner MD, Regan F. Williams MD, Junfang Zhou MD & Andrew M. Davidoff MD

  3. Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Rebecca A. Bush MS & Mary K. Danks PhD

  4. Institute for Regenerative Medicine, Gachon University Gil Hospital, Inchon, Korea

    Seung U. Kim PhD

  5. Department of Medicine, University of British Columbia, Koerner Pavilion, 211 Wesbrook Mall, Vancouver, BC, Canada, V6T 2B5

    Seung U. Kim PhD

  6. Division of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, 1500 E Duarte Road, Duarte, CA, 91010, USA

    Karen S. Aboody PhD

Authors
  1. Thomas L. Sims Jr. MD
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  2. John B. Hamner MD
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  3. Rebecca A. Bush MS
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  9. Andrew M. Davidoff MD
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Correspondence to Andrew M. Davidoff MD.

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Sims, T.L., Hamner, J.B., Bush, R.A. et al. Neural Progenitor Cell-mediated Delivery of Interferon Beta Improves Neuroblastoma Response to Cyclophosphamide. Ann Surg Oncol 15, 3259–3267 (2008). https://doi.org/10.1245/s10434-008-0103-z

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  • DOI: https://doi.org/10.1245/s10434-008-0103-z

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