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

Eric Yvon, Michele Del Vecchio, Barbara Savoldo, Valentina Hoyos, Aurélie Dutour, Andrea Anichini, Gianpietro Dotti, Malcolm K. Brenner

Research output: Contribution to journalArticlepeer-review

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 ζ-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.

Original languageEnglish
Pages (from-to)5852-5860
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number18
DOIs
Publication statusPublished - Sep 15 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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