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Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy

Nature Biotechnologyvolume 23pages14071413 (2005) | Download Citation

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Abstract

The success of cellular therapies will depend in part on accurate delivery of cells to target organs. In dendritic cell therapy, in particular, delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. We show here that in vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information. Autologous dendritic cells were labeled with a clinical superparamagnetic iron oxide formulation or 111In-oxine and were co-injected intranodally in melanoma patients under ultrasound guidance. In contrast to scintigraphic imaging, magnetic resonance imaging (MRI) allowed assessment of the accuracy of dendritic cell delivery and of inter- and intra-nodal cell migration patterns. MRI cell tracking using iron oxides appears clinically safe and well suited to monitor cellular therapy in humans.

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References

  1. 1

    Figdor, C.G., de Vries, I.J., Lesterhuis, W.J. & Melief, C.J. Dendritic cell immunotherapy: mapping the way. Nat. Med. 10, 475–480 (2004).

  2. 2

    Adema, G.J., de Vries, I.J., Punt, C.J. & Figdor, C.G. Migration of dendritic cell based cancer vaccines: in vivo veritas? Curr. Opin. Immunol. 17, 170–174 (2005).

  3. 3

    de Vries, I.J. et al. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res. 63, 12–17 (2003).

  4. 4

    Nair, S. et al. Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J. Immunol. 171, 6275–6282 (2003).

  5. 5

    Blocklet, D. et al. 111In-oxine and 99mTc-HMPAO labelling of antigen-loaded dendritic cells: in vivo imaging and influence on motility and actin content. Eur. J. Nucl. Med. Mol. Imaging 30, 440–447 (2003).

  6. 6

    Bulte, J.W. & Kraitchman, D.L. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 17, 484–499 (2004).

  7. 7

    Stark, D.D. et al. Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. Radiology 168, 297–301 (1988).

  8. 8

    Weissleder, R. et al. Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology 175, 494–498 (1990).

  9. 9

    Harisinghani, M.G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N. Engl. J. Med. 348, 2491–2499 (2003).

  10. 10

    Weissleder, R. et al. Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am. J. Roentgenol. 152, 167–173 (1989).

  11. 11

    Bulte, J.W. et al. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat. Biotechnol. 19, 1141–1147 (2001).

  12. 12

    Bulte, J.W. et al. Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc. Natl. Acad. Sci. USA 96, 15256–15261 (1999).

  13. 13

    Kraitchman, D.L. et al. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107, 2290–2293 (2003).

  14. 14

    Hoehn, M. et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc. Natl. Acad. Sci. USA 99, 16267–16272 (2002).

  15. 15

    Kircher, M.F. et al. In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors. Cancer Res. 63, 6838–6846 (2003).

  16. 16

    Anderson, S.A. et al. Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 105, 420–425 (2005).

  17. 17

    Anderson, S.A. et al. Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann. Neurol. 55, 654–659 (2004).

  18. 18

    Yeh, T.C., Zhang, W., Ildstad, S.T. & Ho, C. In vivo dynamic MRI tracking of rat T-cells labeled with superparamagnetic iron-oxide particles. Magn. Reson. Med. 33, 200–208 (1995).

  19. 19

    Ahrens, E.T., Feili-Hariri, M., Xu, H., Genove, G. & Morel, P.A. Receptor-mediated endocytosis of iron-oxide particles provides efficient labeling of dendritic cells for in vivo MR imaging. Magn. Reson. Med. 49, 1006–1013 (2003).

  20. 20

    de Vries, I.J. et al. Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin. Cancer Res. 9, 5091–5100 (2003).

  21. 21

    Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

  22. 22

    Bakker, A.B. et al. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J. Exp. Med. 179, 1005–1009 (1994).

  23. 23

    Bulte, J.W., Arbab, A.S., Douglas, T. & Frank, J.A. Preparation of magnetically labeled cells for cell tracking by magnetic resonance imaging. Methods Enzymol. 386, 275–299 (2004).

  24. 24

    Hill, J.M. et al. Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108, 1009–1014 (2003).

  25. 25

    Balch, C.M. et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J. Clin. Oncol. 19, 3635–3648 (2001).

  26. 26

    de Vries, I.J. et al. Phenotypical and functional characterization of clinical grade dendritic cells. J. Immunother. 25, 429–438 (2002).

  27. 27

    Thurner, B. et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J. Exp. Med. 190, 1669–1678 (1999).

  28. 28

    Bulte, J.W., Miller, G.F., Vymazal, J., Brooks, R.A. & Frank, J.A. Hepatic hemosiderosis in non-human primates: quantification of liver iron using different field strengths. Magn. Reson. Med. 37, 530–536 (1997).

  29. 29

    Hennig, J. & Scheffler, K. Hyperechoes. Magn. Reson. Med. 46, 6–12 (2001).

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Acknowledgements

Nicole Scharenborg, Mary-lène Brouwer, Annemiek de Boer, Mandy van de Rakt, Mariëlle Philippens, Giulio Gambarota, Andor Veltien, Simon Strijk, Sandra Croockewit, Jos Rijntjes, Emile Koenders, Peter Laverman and Hans Jacobs are acknowledged for their assistance. This work was supported by grants KUN 1999/1950 and 2004/3126 from the Dutch Cancer Society, grant 920-03-250 from the Netherlands Organization for Scientific Research, grants NGT.6719 and NGT.6721 of the Dutch Program for Tissue Engineering, the TIL-foundation, NOTK-foundation and NIH RO1 NS045062. The authors are grateful to Richard A.J. Janssen for his contribution in the initiation of this work.

Author information

Affiliations

  1. Department of Tumor Immunology, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • I Jolanda M de Vries
    • , Pauline Verdijk
    • , Gosse J Adema
    •  & Carl G Figdor
  2. Department of Pediatric Oncology, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • I Jolanda M de Vries
  3. Department of Medical Oncology, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • W Joost Lesterhuis
    •  & Cornelis J A Punt
  4. Department of Radiology, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • Jelle O Barentsz
    • , Tom W J Scheenen
    •  & Arend Heerschap
  5. Department of Pathology, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • J Han van Krieken
  6. Department of Nuclear Medicine, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • Otto C Boerman
    •  & Wim J G Oyen
  7. Department of Surgery, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • Johannes J Bonenkamp
  8. Central Hematological Laboratory, Radboud University Nijmegen Medical Center and Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen, 6500 HB, The Netherlands

    • Jan B Boezeman
  9. The Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, and Institute for Cell Engineering, Johns Hopkins University School of Medicine, 217 Traylor, 720 Rutland Ave., Baltimore, 21205, Maryland, USA

    • Jeff W M Bulte

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jeff W M Bulte or Carl G Figdor.

Supplementary information

  1. Supplementary Fig. 1

    Monitoring of in vivo migration of SPIO and 111In-labeled DCs with MR imaging and scintigraphy. (PDF 523 kb)

  2. Supplementary Fig. 2

    Number of LN positive for labeled DC imaged with MR and scintigraphy. (PDF 38 kb)

  3. Supplementary Video 1

    A movie of MR images showing the LN injected with SPIO-labeled DCs (injection site) and three surrounding LNs (migration sites). (MOV 931 kb)

  4. Supplementary Video 2

    MR images of sequential slices through a LN injected with SPIO-labeled cells and a draining LN. (MOV 885 kb)

  5. Supplementary Video 3

    MR images of sequential slices through a following LN beyond the injection node. (MOV 724 kb)

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DOI

https://doi.org/10.1038/nbt1154

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