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

Nat Med. 2006 Jun;12(6):693-8. doi: 10.1038/nm1405. Epub 2006 May 7.


Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. 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)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / immunology
  • Antibodies, Monoclonal* / therapeutic use
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, SCID
  • Neoplasm Transplantation
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Survival Rate
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / immunology


  • Antibodies, Monoclonal
  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfrsf10b protein, mouse
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma