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

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

Author information

  • 1Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. exyvon@txccc.org

Abstract

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.

PMID:
19737958
[PubMed - indexed for MEDLINE]
PMCID:
PMC2745508
Free PMC Article
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