Advertisement

Journal of Clinical Immunology

, Volume 31, Issue 4, pp 710–718 | Cite as

Trafficking of CAR-Engineered Human T Cells Following Regional or Systemic Adoptive Transfer in SCID Beige Mice

  • Ana Caterina Parente-Pereira
  • Jerome Burnet
  • David Ellison
  • Julie Foster
  • David Marc Davies
  • Sjoukje van der Stegen
  • Sophie Burbridge
  • Laura Chiapero-Stanke
  • Scott Wilkie
  • Stephen Mather
  • John Maher
Article

Abstract

Adoptive immunotherapy using chimeric antigen receptor-engrafted T cells is a promising emerging therapy for cancer. Prior to clinical testing, it is mandatory to evaluate human therapeutic cell products in meaningful in vivo pre-clinical models. Here, we describe the use of fused single-photon emission CT–CT imaging to monitor real-time migration of chimeric antigen receptor-engineered T cells in immune compromised (SCID Beige) mice. Following intravenous administration, human T cells migrate in a highly similar manner to that reported in man, but penetrate poorly into established tumors. By contrast, when delivered via intraperitoneal or subcutaneous routes, T cells remain at the site of inoculation with minimal systemic absorption—irrespective of the presence or absence of tumor. Together, these data support the validity of pre-clinical testing of human T-cell immunotherapy in SCID Beige mice. In light of their established efficacy, regional administration of engineered human T cells represents an attractive therapeutic option to minimize toxicity in the treatment of selected malignancies.

Keywords

Adoptive immunotherapy chimeric antigen receptor SPECT-CT 

Notes

Acknowledgements

We are very grateful to Dr Joy Burchell and Prof Joyce Taylor-Papadimitriou for provision of several highly useful MUC1-related reagents. This work was supported by the US Department of Defense (Fiscal Year 2008 Ovarian Cancer Research Program, Translational Research Partnership Award) under contract W81XWH-09-1-0096; Breast Cancer Campaign (project grant 2006NovPR18), Association for International Cancer Research (project grant 08-0419), Guy’s and St Thomas’ Charity, Experimental Cancer Medicine Centre (King’s College London) and from Guy’s and the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

References

  1. 1.
    Sprangers B, Van Wijmeersch B, Fevery S, Waer M, Billiau AD. Experimental and clinical approaches for optimization of the graft-versus-leukemia effect. Nat Clin Pract Oncol. 2007;4:404–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol. 2009;21:233–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Schmitt TM, Ragnarsson GB, Greenberg PD. T cell receptor gene therapy for cancer. Hum Gene Ther. 2009;20:1240–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Sadelain M. T-cell engineering for cancer immunotherapy. Cancer J. 2009;15:451–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Davies DM, Maher J. Adoptive T-cell immunotherapy of cancer using chimeric antigen receptor-grafted T-cells. Arch Immunol Ther Exp. 2010;58:165–78.CrossRefGoogle Scholar
  6. 6.
    Varela-Rohena A, Molloy PE, Dunn SM, Li Y, Suhoski MM, Carroll RG, et al. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med. 2008;14:1390–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim R, Emi M, Tanabe K, Arihiro K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 2006;66:5527–36.PubMedCrossRefGoogle Scholar
  8. 8.
    Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol. 2002;20:70–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Pulè MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther. 2005;12:933–41.PubMedCrossRefGoogle Scholar
  10. 10.
    Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453–64.PubMedCrossRefGoogle Scholar
  11. 11.
    Murphy WJ, Tian ZG, Asai O, Funakoshi S, Rotter P, Henry M, et al. Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice. J Immunol. 1996;156:2104–11.PubMedGoogle Scholar
  12. 12.
    Taub DD, Tsarfaty G, Lloyd AR, Durum SK, Longo DL, Murphy WJ. Growth hormone promotes human T cell adhesion and migration to both human and murine matrix proteins in vitro and directly promotes xenogeneic engraftment. J Clin Invest. 1994;94:293–300.PubMedCrossRefGoogle Scholar
  13. 13.
    Nervi B, Rettig MP, Ritchey JK, Wang HL, Bauer G, Walker J, et al. Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID beta2mnull mice. Exp Hematol. 2007;35:1823–38.PubMedCrossRefGoogle Scholar
  14. 14.
    Santos EB, Yeh R, Lee J, Nikhamin Y, Punzalan B, Punzalan B, et al. Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase. Nat Med. 2009;15:338–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Dobrenkov K, Olszewska M, Likar Y, Shenker L, Gunset G, Cai S, et al. Monitoring the efficacy of adoptively transferred prostate cancer-targeted human T lymphocytes with PET and bioluminescence imaging. J Nucl Med. 2008;49:1162–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Brown CE, Vishwanath RP, Aguilar B, Starr R, Najbauer J, Aboody KS, et al. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol. 2007;179:3332–41.PubMedGoogle Scholar
  17. 17.
    Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, et al. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol. 2008;180:4901–9.PubMedGoogle Scholar
  18. 18.
    Davies DM, Wilkie S, Foster JM, Delinassios G, Chiapero-Stanke L, Burbridge S, et al. Targeting the extended Erbb receptor family using chimeric antigen receptor (CAR)-grafted T-cells as a treatment for head and neck cancer. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research, AACR, Washington, DC, USA, 17–21 April 2010. Abstract no. 1932.Google Scholar
  19. 19.
    Pittet MJ, Grimm J, Berger CR, Tamura T, Wojtkiewicz G, Nahrendorf M, et al. In vivo imaging of T cell delivery to tumors after adoptive transfer therapy. Proc Natl Acad Sci USA. 2007;104:12457–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Wingens M, Walma T, van Ingen H, Stortelers C, van Leeuwen JE, van Zoelen EJ, et al. Structural analysis of an epidermal growth factor/transforming growth factor-alpha chimera with unique ErbB binding specificity. J Biol Chem. 2003;278:39114–23.PubMedCrossRefGoogle Scholar
  21. 21.
    Wilkie S, Burbridge SE, Chiapero-Stanke L, Pereira AC, Cleary S, van der Stegen SJ, et al. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J Biol Chem. 2010;285:25538–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Read EJ, Keenan AM, Carter CS, Yolles PS, Davey RJ. In vivo traffic of indium-111-oxine labelled human lymphocytes collected by automated apheresis. J Nucl Med. 1990;31:999–1006.PubMedGoogle Scholar
  23. 23.
    Wagstaff J, Gibson C, Thatcher N, Ford WL, Sharma H, Crowther D. Human lymphocyte traffic assessed by indium 111oxine labelling: clinical observations. Clin Exp Immunol. 1981;43:443–9.PubMedGoogle Scholar
  24. 24.
    Fisher B, Packard BS, Read EJ, Carrasquillo JA, Carter CS, Topalian SL, et al. Tumor localization of adoptively transferred indium-111 labelled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol. 1989;7:250–61.PubMedGoogle Scholar
  25. 25.
    Smith ME, Ford WL. The recirculating lymphocyte pool of the rat: a systematic description of the migratory behaviour of recirculating lymphocytes. Immunology. 1983;49:83–94.PubMedGoogle Scholar
  26. 26.
    Looney MR, Thornton EE, Sen D, Lamm WJ, Glenny RW, Krummel MF. Stabilized imaging of immune surveillance in the mouse lung. Nat Methods. 2011;8:91–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Hamann A, Klugewitz K, Austrup F, Jablonski-Westrich D. Activation induces rapid and profound alterations in the trafficking of T cells. Eur J Immunol. 2000;30:3207–18.PubMedCrossRefGoogle Scholar
  28. 28.
    Staunton DE, Dustin ML, Erickson HP, Springer TA. The arrangement of the immunoglobulin-like domains of ICAM-1 and the binding sites for LFA-1 and rhinovirus. Cell. 1990;61:243–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Aird WC. Phenotypic heterogeneity of the Endothelium. 1. Structure, Function and Mechanisms. Circ Res. 2007;100:158–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18:843–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Heslop HE. Safer CARs. Mol Ther. 2010;18:661–2.PubMedCrossRefGoogle Scholar
  32. 32.
    Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol. 2006;24:e20–2.PubMedCrossRefGoogle Scholar
  33. 33.
    Bernhard H, Neudorfer J, Gebhard K, Conrad H, Hermann C, Nährig J, et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother. 2008;57:271–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Koya RC, Mok S, Comin-Anduix B, Chodon T, Radu CG, Nishimura MI, et al. Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. Proc Natl Acad Sci USA. 2010;107:14286–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther. 2010;18:666–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev. 2000;174:47–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Kershaw MH, Wang G, Westwood JA, Pachynski RK, Tiffany HL, Marincola FM, et al. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther. 2002;13:1971–80.PubMedCrossRefGoogle Scholar
  38. 38.
    Lo AS, Taylor JR, Farzaneh F, Kemeny DM, Dibb NJ, Maher J. Harnessing the tumour-derived cytokine, CSF-1, to co-stimulate T-cell growth and activation. Mol Immunol. 2008;45:1276–87.PubMedCrossRefGoogle Scholar
  39. 39.
    Schliemann C, Palumbo A, Zuberbühler K, Villa A, Kaspar M, Trachsel E, et al. Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood. 2009;113:2275–83.PubMedCrossRefGoogle Scholar
  40. 40.
    Cappuccini F, Lucci 3rd JA, Dett CA, Gatanaga M, Ininns EK, Gatanaga T, et al. Trafficking of syngeneic murine lymphokine activated killer T cells following intraperitoneal administration in normal and tumor bearing mice. Gynecol Oncol. 1992;46:163–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Markman M. Intraperitoneal chemotherapy as primary treatment of advanced ovarian cancer: efficacy, toxicity, and future directions. Rev Recent Clin Trials. 2007;2:169–73.PubMedCrossRefGoogle Scholar
  42. 42.
    Van Elssen CH, Frings PW, Bot FJ, Van de Vijver KK, Huls MB, Meek B, et al. Expression of aberrantly glycosylated Mucin-1 in ovarian cancer. Histopathology. 2010;57:597–606.PubMedCrossRefGoogle Scholar
  43. 43.
    Simpson BJ, Phillips HA, Lessells AM, Langdon SP, Miller WR. c-erbB growth-factor-receptor proteins in ovarian tumours. Int J Cancer. 1995;64:202–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ana Caterina Parente-Pereira
    • 1
  • Jerome Burnet
    • 2
  • David Ellison
    • 2
  • Julie Foster
    • 2
  • David Marc Davies
    • 1
  • Sjoukje van der Stegen
    • 1
  • Sophie Burbridge
    • 1
  • Laura Chiapero-Stanke
    • 1
  • Scott Wilkie
    • 1
  • Stephen Mather
    • 2
  • John Maher
    • 1
    • 3
    • 4
    • 5
  1. 1.The CAR Mechanics GroupKing’s College London School of Medicine, Guy’s Hospital CampusLondonUK
  2. 2.Centre for Molecular Oncology and Imaging, Barts Cancer InstituteQueen Mary University of LondonLondonUK
  3. 3.Department of ImmunologyBarnet and Chase Farm NHS TrustBarnetUK
  4. 4.Department of Clinical Immunology and AllergyKing’s College Hospital NHS Foundation TrustLondonUK
  5. 5.Research Oncology, Division of Cancer StudiesKing’s College London School of Medicine, Guy’s Hospital CampusLondonUK

Personalised recommendations