Adoptive T Cell Immunotherapy of Human Uveal Melanoma Targeting gp100

Abstract

HLA-A*0201-restricted CTL against human gp100 were isolated from HLA-A*0201/Kb (A2/Kb)-transgenic mice immunized with recombinant canarypox virus (ALVAC-gp100). These CTL strongly responded to the gp100154–162 epitope, in the context of both the chimeric A2/Kb and the wild-type HLA-A*0201− molecule, and efficiently lysed human HLA-A*0201+, gp100+ melanoma cells in vitro. The capacity of the CTL to eradicate these tumors in vivo was analyzed in A2/Kb-transgenic transgenic mice that had received a tumorigenic dose of human uveal melanoma cells in the anterior chamber of the eye. This immune-privileged site offered the unique opportunity to graft xenogeneic tumors into immunocompetent A2/Kb-transgenic mice, a host in which they otherwise would not grow. Importantly, systemic (i.v.) administration of the A2/Kb-transgenic gp100154–162-specific CTL resulted in rapid elimination of the intraocular uveal melanomas, indicating that anti-tumor CTL are capable of homing to the eye and exerting their tumoricidal effector function. Flow cytometry analysis of ocular cell suspensions with HLA-A*0201-gp100154–162 tetrameric complexes confirmed the homing of adoptively transferred CTL. Therefore, the immune-privileged state of the eye permitted the outgrowth of xenogeneic uveal melanoma cells, but did not protect these tumors against adoptive immunotherapy with highly potent anti-tumor CTL. These data constitute the first direct indication that immunotherapy of human uveal melanoma may be feasible.