INDUCTION OF TYROSINASE-REACTIVE T-CELLS BY TREATMENT WITH DACARBAZINE, CISPLATIN, INTERFERON-ALPHA + - INTERLEUKIN-2 IN PATIENTS WITH METASTATIC MELANOMA/

We have shown the presence of tyrosinase-reactive T cells in the perip heral blood of melanoma patients, who had been in remission after trea tment with IL-22-containing regimens. In this consecutive study, we an alyzed the T cell response to various peptides derived from tyrosinase in serial blood samples obtained from 7 stage-IV melanoma patients be fore, during and following treatment, All patients were treated within a randomized trial (EORTC 18951) with cisplatin (CDDP), dacarbazine ( DTIC), interferon-alpha (IFN-alpha) +/- interleukin-2 (IL-2), Using an ELISPOT assay detecting peptide-specific IFN-gamma release, we measur ed the T-cell response to 4 different HLA class I-binding peptide epit opes derived from tyrosinase containing an HLA-A2.1-, HLA-A24- or HLA- B44-binding motif in peripheral-blood mononuclear cells (PBMC). In one patient, tyrosinase-reactive T cells were detected before therapy. In 4 out of 7 patients, tyrosinase-reactive T cells against both HLA-A2. 1-binding peptides and the B44-binding peptide became detectable at fr equencies of up to 30 in 5 x 10(5) lymphocytes following treatment, Th ese patients received CDDP, DTIC and IFN-alpha, 2 of them without IL-2 and 2 with IL-2, resulting in one complete remission and 3 partial re missions. Two patients relapsed 8 and 9 months after treatment. At the time of relapse, no T cells reactive with tyrosinase were detectable. Our results show that high frequencies of tyrosinase-reactive T cells in the peripheral blood of melanoma patients can be induced by chemot herapy in combination with IFN-alpha, regardless of concomitant IL-2 a dministration. (C) 1999 Wiley-Liss, Inc.