Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells

Clin Cancer Res. 2009 Sep 15;15(18):5852-60. doi: 10.1158/1078-0432.CCR-08-3163. Epub 2009 Sep 8.


Purpose: Genetic engineering of human T lymphocytes to express tumor-directed chimeric antigen receptors (CAR) can produce antitumor effector cells that bypass tumor immune escape mechanisms that are due to abnormalities in protein-antigen processing and presentation. Moreover, these transgenic receptors can be directed to tumor-associated antigens that are not protein-derived, such as the ganglioside GD2, which is expressed in a high proportion of melanoma cells.

Experimental design: We generated chimeric T cells specific for the ganglioside GD2 by joining an extracellular antigen-binding domain derived from the GD2-specific antibody sc14.G2a to cytoplasmic signaling domains derived from the T-cell receptor zeta-chain, with the endodomains of the costimulatory molecules CD28 and OX40. We expressed this CAR in human T cells and assessed the targeting of GD2-positive melanoma tumors in vitro and in a murine xenograft.

Results: Upon coincubation with GD2-expressing melanoma cells, CAR-GD2 T lymphocytes incorporating the CD28 and OX40 endodomains secreted significant levels of cytokines in a pattern comparable with the cytokine response obtained by engagement of the native CD3 receptor. These CAR-T cells had antimelanoma activity in vitro and in our xenograft model, increasing the survival of tumor-bearing animals.

Conclusion: Redirecting human T lymphocytes to the tumor-associated ganglioside GD2 generates effector cells with antimelanoma activity that should be testable in subjects with disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Gangliosides / genetics*
  • Gangliosides / immunology*
  • Genetic Engineering*
  • Humans
  • Immunotherapy*
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / therapy
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / immunology*
  • Xenograft Model Antitumor Assays


  • Antibodies
  • Gangliosides
  • Receptors, Antigen, T-Cell
  • ganglioside, GD2