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Adoptive T Cell Immunotherapy of Human Uveal Melanoma Targeting gp100¹

Roger P. M. Sutmuller^*, Luc R. H. M. Schurmans, Leonie M. van Duivenvoorde^*, John A. Tine, Ellen I. H. van der Voort^*, René E. M. Toes^*, Cornelis J. M. Melief^*, Martine J. Jager and Rienk Offringa^2,*

^* Department of Immunohematology and Bloodbank, Leiden University Medical Center, The Netherlands; Department of Ophthalmology, Leiden University Medical Center, The Netherlands; and Virogenetics Corporation, Troy, NY 12180

HLA-A*0201-restricted CTL against human gp100 were isolated from HLA-A*0201/K^b (A2/K^b)-transgenic mice immunized with recombinant canarypox virus (ALVAC-gp100). These CTL strongly responded to the gp100^154–162 epitope, in the context of both the chimeric A2/K^b 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/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/K^b-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.