Immunotherapy of Metastatic Melanoma Using Genetically Engineered GD2-Specific T cells

• Published in: Clinical cancer research Vol. 15; no. 18; pp. 5852 - 5860
• Main Authors: Yvon, Eric, Del Vecchio, Michele, Savoldo, Barbara, Hoyos, Valentina, Dutour, Aurélie, Anichini, Andrea, Dotti, Gianpietro, Brenner, Malcolm K.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2009
• Subjects: Animals; Antibodies - immunology; Antineoplastic agents; Biological and medical sciences; chimeric antigen receptor; Dermatology; Disialoganglioside GD2; Gangliosides - genetics; Gangliosides - immunology; Genetic Engineering; Humans; Immunotherapy; Medical sciences; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Metastatic melanoma; Mice; Mice, SCID; Neoplasm Metastasis - immunology; Neoplasm Metastasis - therapy; Pharmacology. Drug treatments; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes - immunology; Tumors of the skin and soft tissue. Premalignant lesions; Xenograft Model Antitumor Assays; Treatment; Immunotherapy; T-Lymphocyte; Malignant melanoma; Tissue specificity; Advanced stage; Genetic engineering; Malignant tumor; Metastasis; Cancer
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-3163

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. (Clin Cancer Res 2009;15(18):5852–60)