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


METHODS
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.


CONCLUSIONS
Redirecting human T lymphocytes to the tumor-associated ganglioside GD2 generates effector cells with antimelanoma activity that should be testable in subjects with disease.
Yvon
Eric
E
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. exyvon@txccc.org
Del Vecchio
Michele
M
Savoldo
Barbara
B
Hoyos
Valentina
V
Dutour
Aurélie
A
Anichini
Andrea
A
Dotti
Gianpietro
G
Brenner
Malcolm K
MK
D000818:Animals; D000906:Antibodies / Q000276:immunology; D005732:Gangliosides / Q000235:genetics* / Q000276:immunology*; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000276:immunology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D005732:Gangliosides; D011948:Receptors, Antigen, T-Cell; C019403:ganglioside, GD2