Adaptive T cell immunotherapy of human uveal melanoma targeting gp100

HLA-A*0201-restricted CTL against human gp100 were isolated from HLA-A*0201/K-b (A2/K-b)-transgenic mice immunized,vith recombinant canarypox virus (ALVAC-gp100), These CTL strongly responded to the pp100(154-162) epitope, in the contest of both the chimeric A2/K-b and the wild-type HLA-A*0201- molecule, and efficiently lysed human HLA-A*O0201(+), gp100(+) melanoma cells in vitro. The capacity of the CTL to eradicate these tumors in vivo was analyzed in A2/K-b-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/K-b-transgenic gp100(154-162)-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-gp100(154-162) 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.