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Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells

Abstract

The fiber-modified adenoviral vector Δ-24-RGD (D24RGD) offers vast therapeutic potential. Direct injection of D24RGD has been used to successfully target ovarian tumors in mice. However, systemic toxicity, especially in the liver, profoundly limits the efficacy of direct viral vector delivery. Mesenchymal stem cells (MSC) have the ability to function as a vector for targeted gene therapy because of their preferential engraftment into solid tumors and participation in tumor stroma formation. We show that MSC-guided delivery of D24RGD is specific and efficient and reduces the overall systemic toxicity in mice to negligible levels compared with D24RGD alone. In our model, we found efficient targeted delivery of MSC-D24RGD to both breast and ovarian cell lines. Furthermore, immunohistochemical staining for adenoviral hexon protein confirmed negligible levels of systemic toxicity in mice that were administered MSC-D24RGD compared with those that were administered D24RGD. These data suggest that delivery of D24RGD through MSC not only increases the targeted delivery efficiency, but also reduces the systemic exposure of the virus, thereby reducing overall systemic toxicity to the host and ultimately enhancing its value as an anti-tumor therapeutic candidate.

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References

  1. Heise C, Hermiston T, Johnson L, Brooks G, Sampson-Johannes A, Williams A et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med 2000; 6: 1134–1139.

    Article  CAS  Google Scholar 

  2. Kelly FJ, Miller CR, Buchsbaum DJ, Gomez-Navarro J, Barnes MN, Alvarez RD et al. Selectivity of tag-72-targeted adenovirus gene transfer to primary ovarian carcinoma cells versus autologous mesothelial cells in vitro. Clin Cancer Res 2000; 6: 4323–4333.

    CAS  PubMed  Google Scholar 

  3. Tsuda H, Wada T, Ito Y, Uchida H, Dehari H, Nakamura K et al. Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Mol Ther 2003; 7: 354–365.

    Article  CAS  Google Scholar 

  4. Hemminki A, Belousova N, Zinn KR, Liu B, Wang M, Chaudhuri TR et al. An adenovirus with enhanced infectivity mediates molecular chemotherapy of ovarian cancer cells and allows imaging of gene expression. Mol Ther 2001; 4: 223–231.

    Article  CAS  Google Scholar 

  5. Bauerschmitz GJ, Kanerva A, Wang M, Herrmann I, Shaw DR, Strong TV et al. Evaluation of a selectively oncolytic adenovirus for local and systemic treatment of cervical cancer. Int J Cancer 2004; 111: 303–309.

    Article  CAS  Google Scholar 

  6. Fueyo J, Alemany R, Gomez-Manzano C, Fuller GN, Khan A, Conrad CA et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst 2003; 95: 652–660.

    Article  CAS  Google Scholar 

  7. Stolarek R, Gomez-Manzano C, Jiang H, Suttle G, Lemoine MG, Fueyo J . Robust infectivity and replication of Delta-24 adenovirus induce cell death in human medulloblastoma. Cancer Gene Ther 2004; 11: 713–720.

    Article  CAS  Google Scholar 

  8. Bauerschmitz GJ, Lam JT, Kanerva A, Suzuki K, Nettelbeck DM, Dmitriev I et al. Treatment of ovarian cancer with a tropism modified oncolytic adenovirus. Cancer Res 2002; 62: 1266–1270.

    CAS  PubMed  Google Scholar 

  9. Wang Y, Hu JK, Krol A, Li YP, Li CY, Yuan F . Systemic dissemination of viral vectors during intratumoral injection. Mol Cancer Ther 2003; 2: 1233–1242.

    CAS  PubMed  Google Scholar 

  10. Yu P, Wang X, Fu Y . Enhanced local delivery with reduced systemic toxicity: delivery, delivery, and delivery. Gene Therapy 2006; 13: 1131–1132.

    Article  CAS  Google Scholar 

  11. Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T et al. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther 2007; 14: 894–903.

    Article  CAS  Google Scholar 

  12. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96: 1593–1603.

    Article  CAS  Google Scholar 

  13. Hall B, Dembinski J, Sasser AK, Studeny M, Andreeff M, Marini F . Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007; 86: 8–16.

    Article  CAS  Google Scholar 

  14. Hall B, Andreeff M, Marini F . The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb Exp Pharmacol 2007; 180: 263–283.

    Article  CAS  Google Scholar 

  15. Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F . Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Therapy 2008; 15: 730–738.

    Article  CAS  Google Scholar 

  16. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M . Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002; 62: 3603–3608.

    CAS  Google Scholar 

  17. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96: 1593–1603.

    Article  CAS  Google Scholar 

  18. Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L . Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther 2006; 5: 755–766.

    Article  CAS  Google Scholar 

  19. Kirn D . Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer. Oncogene 2000; 19: 6660–6669.

    Article  CAS  Google Scholar 

  20. Stoff-Khalili MA, Rivera AA, Le LP, Stoff A, Everts M, Contreras JL et al. Employment of liver tissue slice analysis to assay hepatotoxicity linked to replicative and nonreplicative adenoviral agents. Cancer Gene Ther 2006; 13: 606–618.

    Article  CAS  Google Scholar 

  21. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65: 3307–3318.

    Article  CAS  Google Scholar 

  22. Hakkarainen T, Sarkioja M, Lehenkari P, Miettinen S, Ylikomi T, Suuronen R et al. Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors. Hum Gene Ther 2007; 18: 627–641.

    Article  CAS  Google Scholar 

  23. Larochelle A, Dunbar CE . Genetic manipulation of hematopoietic stem cells. Semin Hematol 2004; 41: 257–271.

    Article  CAS  Google Scholar 

  24. Roni V, Habeler W, Parenti A, Indraccolo S, Gola E, Tosello V et al. Recruitment of human umbilical vein endothelial cells and human primary fibroblasts into experimental tumors growing in SCID mice. Exp Cell Res 2003; 287: 28–38.

    Article  CAS  Google Scholar 

  25. Del Rio M, Gache Y, Jorcano JL, Meneguzzi G, Larcher F . Current approaches and perspectives in human keratinocyte-based gene therapies. Gene Therapy 2004; 11 (Suppl 1): S57–S63.

    Article  CAS  Google Scholar 

  26. Li S, Kimura E, Fall BM, Reyes M, Angello JC, Welikson R et al. Stable transduction of myogenic cells with lentiviral vectors expressing a minidystrophin. Gene Therapy 2005; 12: 1099–1108.

    Article  CAS  Google Scholar 

  27. Pereboeva L, Komarova S, Mikheeva G, Krasnykh V, Curiel DT . Approaches to utilize mesenchymal progenitor cells as cellular vehicles. Stem Cells 2003; 21: 389–404.

    Article  CAS  Google Scholar 

  28. Egan C, Jelsma TN, Howe JA, Bayley ST, Ferguson B, Branton PE . Mapping of cellular protein-binding sites on the products of early-region 1A of human adenovirus type 5. Mol Cell Biol 1988; 8: 3955–3959.

    Article  CAS  Google Scholar 

  29. Yotnda P, Zompeta C, Heslop HE, Andreeff M, Brenner MK, Marini F . Comparison of the efficiency of transduction of leukemic cells by fiber-modified adenoviruses. Hum Gene Ther 2004; 15: 1229–1242.

    Article  CAS  Google Scholar 

  30. Fueyo J, Gomez-Manzano C, Alemany R, Lee PSY, McDonnell TJ, Mitlianga P et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000; 19: 2–12.

    Article  CAS  Google Scholar 

  31. Suzuki K, Fueyo J, Krasnykh V, Reynolds PN, Curiel DT, Alemany R . A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. Clin Cancer Res 2001; 7: 120–126.

    CAS  PubMed  Google Scholar 

  32. Lee K, Majumdar MK, Buyaner D, Hendricks JK, Pittenger MF, Mosca JD . Human mesenchymal stem cells maintain transgene expression during expansion and differentiation. Mol Ther 2001; 3: 857–866.

    Article  CAS  Google Scholar 

  33. Liechty KW, Mackenzie TC, Shaaban AF, Radu A, Moseley AB, Deans R et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000; 6: 1282–1286.

    Article  CAS  Google Scholar 

  34. Devine SM, Bartholomew AM, Mahmud N, Nelson M, Patil S, Hardy W et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001; 29: 244–255.

    Article  CAS  Google Scholar 

  35. Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS . Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells 2008; 26: 831–841.

    Article  CAS  Google Scholar 

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Correspondence to F C Marini.

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Dembinski, J., Spaeth, E., Fueyo, J. et al. Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells. Cancer Gene Ther 17, 289–297 (2010). https://doi.org/10.1038/cgt.2009.67

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