Skip to main content

Advertisement

SpringerLink
Log in

Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer

  • Short Communication
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated antigen by immunotherapeutical approaches based on HER2-directed monoclonal antibodies and cancer vaccines. We describe the adoptive transfer of autologous HER2-specific T-lymphocyte clones to a patient with metastatic HER2-overexpressing breast cancer. The HLA/multimer-based monitoring of the transferred T lymphocytes revealed that the T cells rapidly disappeared from the peripheral blood. The imaging studies indicated that the T cells accumulated in the bone marrow (BM) and migrated to the liver, but were unable to penetrate into the solid metastases. The disseminated tumor cells in the BM disappeared after the completion of adoptive T-cell therapy. This study suggests the therapeutic potential for HER2-specific T cells for eliminating disseminated HER2-positive tumor cells and proposes the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

HER2:

Human epidermal growth factor receptor 2

111In:

Indium-111

SPECT:

Single photon emission computed tomography

MRI:

Magnetic resonance tomography

FDG-PET:

[18F] Fluorodeoxyglucose positron emission tomography

MNC:

Mononuclear cell

References

  1. Qin Z, Blankenstein T (2004) A cancer immunosurveillance controversy. Nat Immunol 5:3–4

    Article  PubMed  CAS  Google Scholar 

  2. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677–685

    Article  PubMed  CAS  Google Scholar 

  3. Jäger E, Nagata Y, Gnjatic S, Wada H, Stockert E, Karbach J, Dunbar PR, Lee SY, Jungblut A, Jäger D, Arand M, Ritter G, Cerundolo V, Dupont B, Chen Y-T, Old LJ, Knuth A (2000) Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci USA 97:4760–4765

    Article  PubMed  Google Scholar 

  4. Willimsky G, Blankenstein T (2005) Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437:141–146

    Article  PubMed  CAS  Google Scholar 

  5. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213

    Article  PubMed  CAS  Google Scholar 

  6. Öhlén C, Kalos M, Hong DJ, Shur AC, Greenberg PD (2001) Expression of a tolerizing tumor antigen in peripheral tissue does not preclude recovery of high-affinity CD8+ T cells or CTL immunotherapy of tumors expressing the antigen. J Immunol 166:2863–2870

    PubMed  Google Scholar 

  7. Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan S, Sutton SE, Cooke MP, Öhlén C, Greenberg PD (2006) Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12:335–341

    Article  PubMed  CAS  Google Scholar 

  8. Bollard CM, Aguilar L, Straathof KC, Gahn B, Huls MH, Rousseau A, Sixbey J, Gresik MV, Carrum G, Hudson M, Dilloo D, Gee A, Brenner MK, Rooney CM, Heslop HE (2004) Cytotoxic T lymphocyte therapy for Epstein–Barr virus Hodgkin’s disease. J Exp Med 200:1623–1633

    Article  PubMed  CAS  Google Scholar 

  9. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. PNAS 99:16168–16173

    Article  PubMed  CAS  Google Scholar 

  10. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854

    Article  PubMed  CAS  Google Scholar 

  11. Meidenbauer N, Marienhagen J, Laumer M, Vogl S, Heymann J, Andreesen R, Mackensen A (2003) Survival and tumor localization of adoptively transferred melan-A-specific T cells in melanoma patients. J Immunol 170:2161–2169

    PubMed  CAS  Google Scholar 

  12. Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K (2002) Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20:2624–2632

    Article  PubMed  CAS  Google Scholar 

  13. Blankenstein T (2005) The role of tumor stroma in the interaction between tumor and immune system. Curr Opin Immunol 17:180–186

    Article  PubMed  CAS  Google Scholar 

  14. Knabel M, Franz TJ, Schiemann M, Wulf A, Villmow B, Schmidt B, Bernhard H, Wagner H, Busch DH (2002) Reversible MHC multimer staining for functional isolation of T-cell populations and effective adoptive transfer. Nat Med 8:631–637

    Article  PubMed  CAS  Google Scholar 

  15. Meyer zum Büschenfelde C, Metzger J, Hermann C, Nicklisch N, Peschel C, Bernhard H (2001) The generation of both T killer and T helper cell clones specific for the tumor-associated antigen HER2 using retrovirally transduced dendritic cells. J Immunol 167:1712–1719

    Google Scholar 

  16. Walker BD, Flexner C, Birch-Limberger K, Fisher L, Paradis TJ, Aldovini A, Young R, Moss B, Schooley RT (1989) Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc Natl Acad Sci USA 86:9514–9518

    Article  PubMed  CAS  Google Scholar 

  17. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes C, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga J-Y, Marth C, Oruzio D, Wiedswang G, Solomayer E-F, Kundt G, Strobl B, Fehm T, Wong GYC, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802

    Article  PubMed  CAS  Google Scholar 

  18. Fisk B, Blevins TL, Wharton JT, Ioannides CG (1995) Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 181:2109–2117

    Article  PubMed  CAS  Google Scholar 

  19. Neudorfer J, Schmidt B, Huster KM, Anderl F, Schiemann M, Holzapfel G, Schmidt T, Germeroth L, Wagner H, Peschel C, Busch DH, Bernhard H (2007) Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens. J Immunol Methods 320:119–131

    Article  PubMed  CAS  Google Scholar 

  20. Rongcun Y, Salazar-Onfray F, Charo J, Malmberg K-J, Evrin K, Maes H, Kono K, Hising C, Petersson M, Larsson O, Lan L, Appella E, Sette A, Celis E, Kiesling R (1999) Identification of new HER2/neu-derived peptide epitopes that can elicit specific CTL against autologous and allogeneic carcinomas and melanomas. J Immunol 163:1037–1044

    PubMed  CAS  Google Scholar 

  21. Zaks TZ, Rosenberg SA (1998) Immunization with a peptide epitope (p369–377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors. Cancer Res 58:4902–4908

    PubMed  CAS  Google Scholar 

  22. Herrmann F, Lehr H-A, Drexler I, Sutter G, Hengstler J, Wollscheid U, Seliger B (2004) HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway. Cancer Res 64:215–220

    Article  PubMed  CAS  Google Scholar 

  23. Castilleja A, Carter D, Efferson CL, Ward NE, Kawano K, Fisk B, Kudelka AP, Gershenson DM, Muarray JL, O’Brian CA, Ioannides CG (2002) Induction of tumor-reactive CTL by c-side chain variants of the CTL epitope HER-2/neu protooncogene (369–377) selected by molecular modeling of the peptide: HLA-A2 complex. J Immunol 169:3545–3554

    PubMed  CAS  Google Scholar 

  24. Vertuani S, Sette A, Sidney J, Southwood S, Fikes J, Keogh E, Lindencrona JA, Ishioka G, Levitskaya J, Kiessling R (2004) Improved immunogenicity of an immunodominant epitope of the Her-2/neu protooncogene by alterations of MHC contact residues. J Immunol 172:3501–3508

    PubMed  CAS  Google Scholar 

  25. Lustgarten J, Dominguez AL, Pinilla C (2006) Identification of cross-reactive peptides using combinatorial libraries circumvents tolerance against Her-2/neu-immunodominant epitope. J Immunol 176:1796–1805

    PubMed  CAS  Google Scholar 

  26. Müller MR, Grünebach F, Nencioni A, Brossart P (2003) Transfection of dendritic cells with RNA induces CD4- and CD8-mediated T cell immunity against breast carcinomas and reveals the immunodominance of presented T cell epitopes. J Immunol 170:5892–5896

    PubMed  Google Scholar 

  27. Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ (2002) Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 62:1462–1470

    PubMed  CAS  Google Scholar 

  28. Padera TP, Stoll BR, Tooredman JB, Capen D, diTomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695

    Article  PubMed  CAS  Google Scholar 

  29. Garbi N, Arnold B, Gordon S, Hämmerling GJ, Ganss R (2004) CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction. J Immunol 172:5861–5869

    PubMed  CAS  Google Scholar 

  30. Feuerer M, Beckhove P, Bai L, Solomayer E-F, Bastert G, Diel IJ, Pedain C, Oberniedermayr M, Schirrmacher V, Umansky V (2001) Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nature Med 7:452–458

    Article  PubMed  CAS  Google Scholar 

  31. Carson WE, Parihar R, Lindemann MJ, Personeni N, Dierksheide J, Meropol NJ, Baselga J, Caligiuri MA (2001) Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. Eur J Immunol 31:3016–3025

    Article  PubMed  CAS  Google Scholar 

  32. Fleming GF, Meropol NJ, Rosner GL, Hollis DR, Carson WE, Caligiuri M, Mortimer J, Tkaczuk K, Parihar R, Schilsky RL, Ratain MJ (2002) A phase I trial of escalating doses of trastuzumab combined with daily subcutaneous interleukin 2: report of Cancer and Leukemia Group B 9661. Clin Cancer Res 8:3718–3727

    PubMed  CAS  Google Scholar 

  33. Meyer zum Büschenfelde C, Hermann C, Schmidt B, Peschel C, Bernhard H (2002) Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab enhances cytolytic activity of class I-restricted HER2-specific T lymphocytes against HER2-overexpressing tumor cells. Cancer Research 62:2244–2247

    Google Scholar 

  34. Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, Finkelstein SE, Theroret MR, Rosenberg SA, Restifo NP (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 115:1616–1626

    Article  PubMed  CAS  Google Scholar 

  35. Huster KM, Busch V, Schiemann M, Linkemann K, Kerksiek KM, Wagner H, Busch DH (2004) Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. PNAS 101:5610–5615

    Article  PubMed  CAS  Google Scholar 

  36. Robbins PF, Dudley ME, Wunderlich J, El-Gamil M, Li YF, Zhou J, Huang J, Powell DJ, Rosenberg SA (2004) Persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 173:7125–7130

    PubMed  CAS  Google Scholar 

  37. Zhou J, Dudley ME, Rosenberg SA, Robbins PF (2004) Selective growth, in vitro and in vivo, of individual T cell clones from tumor-infiltrating lymphocytes obtained from patients with melanoma. J Immunol 173:7622–7629

    PubMed  CAS  Google Scholar 

  38. Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF (2005) Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol 175:7046–7052

    PubMed  CAS  Google Scholar 

  39. Berger C, Huang M-L, Gough M, Greenberg PD, Riddell SR, Kiem H-P (2000) Nonmyeloablative immunosuppressive regimen prolongs in vivo persistence of gene-modified autologous T cells in a nonhuman primate model. J Virol 75:799–808

    Article  Google Scholar 

  40. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the patients for taking part in this clinical trial; Burkhard Schmidt, Evelyn Schulz and Matthias Schiemann for excellent technical assistance; Peter Schmidkonz for expert clinical care; and Wendy Batten for helpful discussion and critical reading of the manuscript. This work was supported by the Research Council of Germany grant SFB 456 (to H.B. and D.H.B.) and the Wilhelm Sander-Stiftung grant 2000.017.3 (to H.B.).

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, Technical University of Munich, Klinikum rechts der Isar, 81675, Munich, Germany

    Helga Bernhard, Julia Neudorfer, Kerstin Gebhard, Heinke Conrad, Christine Hermann & Christian Peschel

  2. Department of Pathology, Technical University of Munich, Klinikum rechts der Isar, 81675, Munich, Germany

    Jörg Nährig & Falko Fend

  3. Department of Nuclear Medicine, Technical University of Munich, Klinikum rechts der Isar, 81675, Munich, Germany

    Wolfgang Weber

  4. Department of Microbiology, Immunology and Hygiene, Technical University of Munich, Klinikum rechts der Isar, 81675, Munich, Germany

    Dirk H. Busch

  5. Clinical Cooperation Group ‘Antigen-Specific Immunotherapy’, GSF, Institute of Health and Environment Neuherberg and Technical University of Munich, Neuherberg, Germany

    Helga Bernhard, Kerstin Gebhard & Dirk H. Busch

  6. 3rd Medical Department, Technical University of Munich, Ismaninger Straße 22, Klinikum rechts der Isar, 81675, Munich, Germany

    Helga Bernhard

Authors
  1. Helga Bernhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia Neudorfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kerstin Gebhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heinke Conrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christine Hermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jörg Nährig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Falko Fend
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wolfgang Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dirk H. Busch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christian Peschel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helga Bernhard.

Additional information

This manuscript is published with a commentary by Vy Phan and Mary L. Disis entitled “Tumor stromal barriers to the success of adoptive T cell therapy”.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM1 (DOC 40.5 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernhard, H., Neudorfer, J., Gebhard, K. et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother 57, 271–280 (2008). https://doi.org/10.1007/s00262-007-0355-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-007-0355-7

Keywords

Search

Navigation