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Eradication of established tumors in mice by a combination antibody-based therapy

Nature Medicine volume 12, pages 693–698 (2006)Cite this article

Abstract

Tumor-cell apoptosis is the basis of many cancer therapies1,2,3, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies4,5,6,7. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-γ in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-γ in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.*

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Figure 1: Eradication of established 4T1 tumors by trimAb therapy.
Figure 2: Enhanced induction of IFN-γ–producing 4T1 tumor-specific CTLs by trimAb therapy.
Figure 3: DR5-mediated tumor apoptosis is requisite for tumor rejection.
Figure 4: CD8+ T cell–mediated rejection of established MCA-induced primary tumors after treatment with trimAb therapy.

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Notes

  1. NOTE: In the version of this article published online, Figure 2c was incorrectly referenced on page 2. The correct figure reference is to Figure 2d. Also, an abbreviation written incorrectly. On page 2, CTLS should have read CTLs. This has been corrected for all versions of the article.

References

  1. Johnstone, R.W., Ruefli, A.A. & Lowe, S.W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).

    Article  CAS  Google Scholar 

  2. Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer 2, 420–430 (2002).

    Article  CAS  Google Scholar 

  3. Lake, R.A. & Robinson, B.W. Immunotherapy and chemotherapy—a practical partnership. Nat. Rev. Cancer 5, 397–405 (2005).

    Article  CAS  Google Scholar 

  4. Pardoll, D. & Allison, J. Cancer immunotherapy: breaking the barriers to harvest the crop. Nat. Med. 10, 887–892 (2004).

    Article  CAS  Google Scholar 

  5. Rosenberg, S.A., Yang, J.C. & Restifo, N.P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

    Article  CAS  Google Scholar 

  6. Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).

    Article  CAS  Google Scholar 

  7. Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11–22 (2004).

    Article  CAS  Google Scholar 

  8. Smyth, M.J. et al. Nature's TRAIL–on a path to cancer immunotherapy. Immunity 18, 1–6 (2003).

    Article  CAS  Google Scholar 

  9. Wiley, S.R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).

    Article  CAS  Google Scholar 

  10. Pitti, R.M. et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 271, 12687–12690 (1996).

    Article  CAS  Google Scholar 

  11. Walczak, H. et al. Tumoricidal activity of tumor necrosis factor–related apoptosis-inducing ligand in vivo. Nat. Med. 5, 157–163 (1999).

    Article  CAS  Google Scholar 

  12. Chuntharapai, A. et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J. Immunol. 166, 4891–4898 (2001).

    Article  CAS  Google Scholar 

  13. Ichikawa, K. et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat. Med. 7, 954–960 (2001).

    Article  CAS  Google Scholar 

  14. Takeda, K. et al. Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J. Exp. Med. 199, 437–448 (2004).

    Article  CAS  Google Scholar 

  15. French, R.R., Chan, H.T., Tutt, A.L. & Glennie, M.J. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat. Med. 5, 548–553 (1999).

    Article  CAS  Google Scholar 

  16. Melero, I. et al. Monoclonal antibodies against the 4–1BB T-cell activation molecule eradicate established tumors. Nat. Med. 3, 682–685 (1997).

    Article  CAS  Google Scholar 

  17. Selenko, N. et al. CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD8+ cytotoxic T cells. Leukemia 15, 1619–1626 (2001).

    Article  CAS  Google Scholar 

  18. zum Buschenfelde, C.M., Hermann, C., Schmidt, B., Peschel, C. & Bernhard, H. 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 Res. 62, 2244–2247 (2002).

    PubMed  Google Scholar 

  19. Dhodapkar, K.M., Krasovsky, J., Williamson, B. & Dhodapkar, M.V. Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J. Exp. Med. 195, 125–133 (2002).

    Article  CAS  Google Scholar 

  20. Cretney, E. et al. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J. Immunol. 168, 1356–1361 (2002).

    Article  CAS  Google Scholar 

  21. Takeda, K. et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J. Exp. Med. 195, 161–169 (2002).

    Article  CAS  Google Scholar 

  22. Dunn, G.P., Old, L.J. & Schreiber, R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004).

    Article  CAS  Google Scholar 

  23. Noguchi, Y., Jungbluth, A., Richards, E.C. & Old, L.J. Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. Proc. Natl. Acad. Sci. USA 93, 11798–11801 (1996).

    Article  CAS  Google Scholar 

  24. Hayakawa, Y., Rovero, S., Forni, G. & Smyth, M.J. α-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. Proc. Natl. Acad. Sci. USA 100, 9464–9469 (2003).

    Article  CAS  Google Scholar 

  25. Basombrio, M.A. Search for common antigenicities among twenty-five sarcomas induced by methylcholanthrene. Cancer Res. 30, 2458–2462 (1970).

    CAS  PubMed  Google Scholar 

  26. Khong, H.T. & Restifo, N.P. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat. Immunol. 3, 999–1005 (2002).

    Article  CAS  Google Scholar 

  27. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

    Article  CAS  Google Scholar 

  28. Hurwitz, A.A., Yu, T.F., Leach, D.R. & Aliison, J.P. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc. Natl. Acad. Sci. USA 95, 10067–10071 (1998).

    Article  CAS  Google Scholar 

  29. Hixon, J.A. et al. Administration of either anti-CD40 or interleukin-12 following lethal total body irradiation induces acute lethal toxicity affecting the gut. Biol. Blood Marrow Transplant. 8, 316–325 (2002).

    Article  CAS  Google Scholar 

  30. Hamann, U., Eichmann, K. & Krammer, P.H. Frequencies and regulation of trinitrophenyl-specific cytotoxic T precursor cells: immunization results in release from suppression. J. Immunol. 130, 7–14 (1983).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Rolink for monoclonal antibody to mouse CD40 (FGK45). This work was supported by the Ministry of Education, Science, and Culture, Japan. M.J.S. was also supported by a National Health and Medical Research Council of Australia Program Grant and Research Fellowship and the Susan G. Komen Breast Cancer Foundation.

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Authors and Affiliations

  1. Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan

    Tomoyasu Uno, Kazuyoshi Takeda, Hisaya Akiba, Ko Okumura & Hideo Yagita

  2. Department of Homeostatic Regulation and Development, Division of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi 1-757, Niigata, 951-8510, Japan

    Tomoyasu Uno & Fumitake Gejyo

  3. Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002, Victoria, Australia

    Kazuyoshi Takeda & Mark J Smyth

  4. Division of Biomedical Imaging Research, Biomedical Research Center, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan

    Yuko Kojima

  5. Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Asahimachi 1-757, Niigata, Japan, 951-8510, Japan

    Hirohisa Yoshizawa

  6. Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road, Atlanta, 30329, Georgia, USA

    Robert S Mittler

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Correspondence to Kazuyoshi Takeda.

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Supplementary information

Supplementary Fig. 1

Initial tumor cell death induction followed by CD40- and CD137-specific monoclonal antibodies treatment is sufficient for rejection of established tumors. (PDF 1208 kb)

Supplementary Fig. 2

Induction of 4T1 tumor-specific CTL by trimAb therapy. (PDF 1527 kb)

Supplementary Fig. 3

Involvement of IFN-γ and perforin in trimAb-induced tumor rejection. (PDF 755 kb)

Supplementary Methods (PDF 44 kb)

Supplementary Note (PDF 84 kb)

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Uno, T., Takeda, K., Kojima, Y. et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med 12, 693–698 (2006). https://doi.org/10.1038/nm1405

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