Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression

Cancer Gene Therapy volume 15, pages 382–392 (2008)Cite this article

Abstract

In this report, we developed a chimeric receptor (N29γ chR) involving the single chain Fv (scFv) derived from N29 monoclonal antibody (mAb) specific for p185HER2 and characterized the therapeutic efficacy of primary T cells engineered to express N29γ chR in two histologically distinct murine tumor models. Murine breast (MT901) and fibrosarcoma (MCA207) cancer cell lines were engineered to express human HER2 as targets. Administration of N29γ chR-expressing T cells eliminated 3-day pulmonary micrometastases of MT901/HER2 and MCA207/HER2 but not parental tumor cells. A 5 to 8-fold increased dose of N29γ T cells was required to mediate regression of advanced 8-day macrometastases. Exogenous administration of interleukin-2 (IL-2) after N29γ T-cell transfer was dispensable for treatment of 3-day micrometastases, but was required for mediating regression of well-established 8-day macrometastases. Moreover, fractionated CD8 T cells expressing N29γ chR suppressed HER2-positive tumor cell growth after adoptive transfer independent of CD4+ cells. These data indicate that genetically modified T cells expressing a HER2-targeting chimeric receptor can mediate antigen-specific regression of preestablished metastatic cancers in a cell dose-dependent fashion. Systemic administration of IL-2 augments the therapeutic efficacy of these genetically engineered T cells in advanced diseases. These results are relevant to the implication of genetically redirected T cells in clinical cancer immunotherapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Mule JJ, Shu S, Schwarz SL, Rosenberg SA . Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 1984; 225: 1487–1489.

    Article  CAS  PubMed  Google Scholar 

  2. Yannelli JR, Hyatt C, McConnell S, Hines K, Jacknin L, Parker L et al. Growth of tumor-infiltrating lymphocytes from human solid cancers: summary of a 5-year experience. Int J Cancer 1996; 65: 413–421.

    Article  CAS  PubMed  Google Scholar 

  3. Li Q, Grover A, Donald EJ, Carr A, Yu J, Whitfield J et al. Simultaneous targeting of CD3 on T cells and CD40 on B or dendritic cells augments theantitumor reactivity of tumor-primed lymph node cells. J Immunol 2005; 175: 1424–1432.

    Article  CAS  PubMed  Google Scholar 

  4. MacGregor JN, Li Q, Chang AE, Hughes DPM, McDonagh KT . Ex vivo culture with IL-12 improves CD8+ T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFNγ but requires perforin. Cancer Res 2006; 66: 4913–4921.

    Article  CAS  PubMed  Google Scholar 

  5. Chang AE, Li Q, Jiang G, Sayre DM, Braun TM, Redman BG . Phase II trial of autologous tumor vaccination, Anti-CD3-activated vaccine-primed lymphocytes, and interleukin-2 in stage IV renal cell cancer. J Clin Oncol 2003; 21: 884.

    Article  CAS  PubMed  Google Scholar 

  6. Kourilsky P, Jaulin C, Ley V . The structure and function of MHC molecules. Possible implications for the control of tumor growth by MHC-restricted T cells. Semin Cancer Biol 1991; 2: 275–282.

    CAS  PubMed  Google Scholar 

  7. Bodmer WF, Browning MJ, Krausa P, Rowan A, Bicknell DC, Bodmer JG . Tumor escape from immune response by variation in HLA expression and other mechanisms. Ann NY Acad Sci 1993; 690: 42–49.

    Article  CAS  PubMed  Google Scholar 

  8. Restifo N, Marincola F, Kawakami Y, Taubenberger J, Yannelli J, Rosenberg S . Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 1996; 88: 100–108.

    Article  CAS  PubMed  Google Scholar 

  9. Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mule JJ, Rosenberg SA et al. Identification of human cancers deficient in antigen processing. J Exp Med 1993; 177: 265–272.

    Article  CAS  PubMed  Google Scholar 

  10. Roszkowski JJ, Lyons GE, Kast WM, Yee C, Van Besien K, Nishimura MI . Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor. Can Res 2005; 65: 1570–1576.

    Article  CAS  Google Scholar 

  11. Scholten KBJ, Schreurs MWJ, Ruizendaal JJ, Kueter EWM, Kramer D, Veenbergen S et al. Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer. Clin Immunol 2006; 114: 119–129.

    Article  Google Scholar 

  12. Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA et al. Experience with the use of high-dose IL-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roychowdhury S, May Jr KF, Tzou KS, Lin T, Bhatt D, Freud AG et al. Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2. Can Res 2004; 64: 8062.

    Article  CAS  Google Scholar 

  14. Nacsa J, Edghill-Smith Y, Tsai WP, Venzon D, Tryniszewska E, Hryniewicz A et al. Contrasting effects of low-dose IL-2 on vaccine-boosted simian immunodeficiency virus (SIV)-specific CD4+ and CD8+ T cells in macaques chronically infected in SIVmac251. J Immunol 2005; 174: 1913.

    Article  CAS  PubMed  Google Scholar 

  15. Poggi A, Massaro A, Negrini S, Contini P, Zocchi MR . Tumor-induced apoptosis of human IL-2-activated NK cells: role of natural cytotoxicity receptors. J Immunol 2005; 174: 2653.

    Article  CAS  PubMed  Google Scholar 

  16. Brocker T . Chimeric Fv-zeta or Fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood 2000; 96: 1999–2001.

    CAS  PubMed  Google Scholar 

  17. Gritzapis A, Mamalaki A, Kretsovali A, Papamatheakis J, Belimezi M, Perez S et al. Redirecting mouse T hybridoma against human breast and ovarian carcinomas: in vivo activity against HER-2/neu expressing cancer cells. Br J Cancer 2003; 88: 1292–1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stancovski I, Schindler DG, Waks T, Yarden Y, Sela M, Eshhar Z . Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J Immunol 1993; 151: 6577–6582.

    CAS  PubMed  Google Scholar 

  19. Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y, Sela M . Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci USA 1991; 88: 8691–8695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rosenberg S, Yannelli J, Yang J, Topalian S, Schwartzentruber D, Weber J et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 1994; 86: 1159–1166.

    Article  CAS  PubMed  Google Scholar 

  21. Hwu P, Yang T, Cowherd R, Treisman J, Shafer GE, Eshhar Z et al. In vivo antitumor activity of T cells redirected with chimeric antibody/T cell receptor genes. Can Res 1995; 55: 3369–3373.

    CAS  Google Scholar 

  22. Dall P, Herrmann I, Durst B, Stoff-Khalili M, Bauerschmitz G, Hanstein B et al. In vivo cervical cancer growth inhibition by genetically engineered cytotoxic T cells. Cancer Immuno Immunother 2005; 54: 51–60.

    Article  Google Scholar 

  23. Eshhar Z, Waks T, Schindler DG, Gross G . Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody binding domains and the g or z subunits of the immunoglobulin and T cell receptors. Proc Natl Acad Sci USA 1993; 90: 720–724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hwu P, Shafer G, Treisman J . Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor γ chain. J Exp Med 1993; 178: 361–366.

    Article  CAS  PubMed  Google Scholar 

  25. Pinthus JH, Waks T, Kaufman-Francis K, Schindler DG, Harmelin A, Kanety H et al. Immuno-gene therapy of established prostate tumors using chimeric receptor-redirected human lymphocytes. Can Res 2003; 63: 2470–2476.

    CAS  Google Scholar 

  26. Gade TP, Hassen W, Santos E, Gunset G, Saudemont A, Gong MC et al. Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res 2005; 65: 9080–9088.

    Article  CAS  PubMed  Google Scholar 

  27. Kershaw MH, Jackson JT, Haynes NM, Teng MWL, Moeller M, Hayakawa Y et al. Gene-engineered T cells as a superior adjuvant therapy for metastatic cancer. J Immunol 2004; 173: 2143–2150.

    Article  CAS  PubMed  Google Scholar 

  28. Hung MC, Lau YK . Basic science of HER-2/neu: a review. Semin Oncol 1999; 26: 51–59.

    CAS  PubMed  Google Scholar 

  29. Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C, Hadary A . Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 2005; 93: 552–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pusztai L, Esteva F . Continued use of trastuzumab (herceptin) after progression on prior trastuzumab therapy in HER-2-positive metastatic breast cancer. Cancer Invest 2006; 24: 187–191.

    Article  CAS  PubMed  Google Scholar 

  31. Iizuka K, Nakajima C, Iizuka YM, Takase M, Kato T, Noda S et al. Protection from lethal infection by adoptive transfer of CD8 T cells genetically engineered to express virus-specific innate immune receptor. J Immunol 2007; 179: 1122–1128.

    Article  CAS  PubMed  Google Scholar 

  32. Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels WS et al. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res 2007; 67: 5957–5964.

    Article  CAS  PubMed  Google Scholar 

  33. Singh H, Serrano LM, Pfeiffer T, Olivares S, McNamara G, Smith DD et al. Combining adoptive cellular and immunocytokine therapies to improve treatment of B-lineage malignancy. Cancer Res 2007; 67: 2872–2880.

    Article  CAS  PubMed  Google Scholar 

  34. Zhao Y, Parkhurst MR, Zheng Z, Cohen CJ, Riley JP, Gattinoni L et al. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res 2007; 67: 2425–2429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Q, Carr AL, Donald EJ, Skitzki JJ, Okuyama R, Stoolman LM et al. Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. Can Res 2005; 65: 1063.

    Google Scholar 

  36. Hughes DP, Baskar D, Urban FF, Friedman MS, Braun TM, McDonagh KT . Fate and function of anti-CD3/CD28-activated T cells following adoptive transfer: IL-2 promotes development of anti-tumor memory T cells in vivo. Cytotherapy 2005; 7: 396–407.

    Article  CAS  PubMed  Google Scholar 

  37. Li Q, Yu B, Grover AC, Zeng X, Chang AE . Therapeutic effects of tumor-reactive CD4+ cells generated from tumor-primed lymph nodes using anti-CD3/anti-CD28 monoclonal antibodies. J Immunother 2002; 25: 304.

    Article  CAS  PubMed  Google Scholar 

  38. Egilmez NK, Hess SD, Chen FA, Takita H, Conway TF, Bankert RB . Human CD4+ effector T cells mediate indirect interleukin-12-and interferon-γ-dependent suppression of autologous HLA-negative lung tumor xenografts in sever combined immunodeficient mice. Cancer Res 2002; 62: 2611–2617.

    CAS  PubMed  Google Scholar 

  39. Wang S, Boonman ZFHF, Li HC, He Y, Jager MJ, Toes REM et al. Role of TRAIL and IFN-γ in CD4+ T cell-dependent tumor rejection in the anterior chamber of the eye. J Immunol 2003; 171: 2789–2796.

    Article  CAS  PubMed  Google Scholar 

  40. Cardin R, Brooks J, Sarawar S, Doherty P . Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J Exp Med 1996; 184: 863–871.

    Article  CAS  PubMed  Google Scholar 

  41. Stohlman SA, Bergmann CC, Lin MT, Cua DJ, Hinton DR . CTL effector function within the central nervous system requires CD4+ T cells. J Immunol 1998; 160: 2896–2904.

    CAS  PubMed  Google Scholar 

  42. Hombach A, Heuser C, Marquardt T, Wieczarkowiecz A, Groneck V, Pohl C et al. CD4+ T cells engrafted with a recombinant immunoreceptor efficiently lyse target cells in a MHC antigen-and-fas independent fashion. J Immunol 2001; 167: 1090–1096.

    Article  CAS  PubMed  Google Scholar 

  43. Anthony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 2005; 174: 2591–2601.

    Article  Google Scholar 

  44. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996; 14: 737–744.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang T, Barber A, Sentman CL . Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. Can Res 2006; 66: 5927–5933.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Eleanore Kotowski for her excellent assistance in the preparation of this paper.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    S Li, J Yang, F A Urban, J N MacGregor, D P M Hughes & K T Mcdonagh

  2. Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China

    S Li

  3. Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai, China

    J Yang

  4. Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA

    A E Chang & Q Li

  5. Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KT, USA

    K T Mcdonagh

Authors
  1. S Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F A Urban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J N MacGregor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D P M Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A E Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K T Mcdonagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to K T Mcdonagh or Q Li.

Additional information

Disclosure/Conflict of Interest

The authors declare no conflict of financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, S., Yang, J., Urban, F. et al. Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression. Cancer Gene Ther 15, 382–392 (2008). https://doi.org/10.1038/cgt.2008.5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2008.5

Keywords

This article is cited by

Search

Advanced search

Quick links