Tyrosinase reactive T cells can eliminate large established human melanoma tumors in vivo (48.23)

Abstract

Abstract Objective clinical responses of melanoma can be achieved by infusion of tumor infiltrating lymphocytes or T cell receptor (TCR) gene transduced T cells. To evaluate the therapeutic efficacy of T cells expressing a high affinity TCR specific for the tyrosinase melanoma antigen (epitope Tyr368-376), we have developed a xenogenic model of human melanoma. Established human melanoma tumors (624 MEL) were rejected by administering low numbers of TIL 1383I TCR transgenic (h3T) splenocytes in an antigen specific, HLA-A2 restricted manner. Importantly, this therapeutic effect was observed with both small (30mm3) and large (100mm3) tumors. However, many of the mice that rejected their tumors recurred in time and the recurrent tumor cells were no longer recognized by h3T cells in vitro or in vivo. Phenotypic analysis revealed that all recurrent tumors from mice bearing 624 MEL had specifically lost HLA-A2, but not other MHC class I alleles, and this was not restored by IFN-γ treatment. Interestingly, mice bearing a HLA-A2 positive clone of 624 MEL (624-38 MEL) did not exhibit any tumor recurrences when treated with h3T cells. These results highlight the limitations of using a monoclonal therapeutic approach for melanoma. They also stress the need of models that enable us to evaluate combinatory therapies targeting heterogeneous tumors to develop improved immunotherapeutic strategies.