The objective response rate in the sequential cohort was lower at 20%. receptor (an extracellular domain name derived from tumor-specific antibody, linked to an intracellular signaling domain name). One study screened human lymphocytes and also immunized transgenic mice to generate TCRs with high avidity for melanoma-associated antigens (MART-1 and gp100). Genes encoding these TCRs were designed into retroviral vectors and used to transduce autologous peripheral lymphocytes. Objective tumor regressions were seen in 30 and 19% of patients receiving either the human or mouse TCR, respectively. Toxicity was observed in normal tissues including the skin, ear and vision which sometimes required treatment with local steroid therapy?[13]. ??Melanoma vaccines A number of melanoma-specific vaccines have been studied in patients with metastatic disease or in the adjuvant setting with variable success. A vaccine derived from the melanoma antigen glycoprotein 100 (gp100) was analyzed in combination with IL-2 in a Phase III trial?[14]. Patients with metastatic melanoma were randomized to receive IL-2 alone or IL-2 plus the vaccine. The response rate was 16% for the combination arm compared with 6% for IL-2 monotherapy. The response rate was lower than expected for the IL-2 alone arm (which may be due to a altered dosing routine) but the trial did demonstrate improved efficacy with the addition of the vaccine. MAGE-3 is usually expressed on around XR9576 70% of melanoma cells. A XR9576 recombinant MAGE-3 protein vaccine combined with an adjuvant has shown activity in patients with metastatic melanoma and the ability to elicit MAGE-3-specific antibody and a T-cell response in patients?[15]. In a Phase II EORTC study, a gene expression profile was found that was associated with an improved clinical response to the MAGE-3 vaccine. The presence of this gene signature was associated with a significantly prolonged time to treatment failure (10.3 months in those with the characteristic gene signature compared with 2.3 months in those without the signature)?[16,17]. The results of a randomized Phase III trial of the vaccine in resected stage III melanoma are pending, though it has been announced that the first co-primary endpoint was not met?[18]. A polyvalent melanoma cell vaccine consisting of three human melanoma cell lines chosen for their high expression of protein and ganglioside antigens was examined in a Phase II trial. This trial found that the median survival NFIL3 of stage IV patients was prolonged to 23.1 months, compared with 7.5 months in a control group of patients previously treated with predominately chemotherapy or XR9576 intratumoral bacillus CalmetteCGurin (BCG) therapy?[19]. A subsequent Phase III trial of the whole-cell vaccine compared with placebo in resected stage III melanoma failed to show a benefit?[20]. Gangliosides are glycolipids that are overexpressed on the surface of melanoma cells. The presence of antibody to GM2 ganglioside has been associated with prolonged survival in patients with melanoma, and administering a GM2 made up of vaccine is effective in inducing an antibody response to GM2?[21]. However, when the GM2-KLH vaccine was analyzed in two Phase III trials in the adjuvant setting, it failed to show a survival benefit?[22,23]. Phase III trials of vaccines in melanoma have focused on the adjuvant setting and it is not clear why the positive results seen in Phase II trials (often in patients with metastatic disease) did not translate into a clinical benefit in these trials. The Phase III trial of the peptide vaccine gp100 in combination with IL-2 did show a benefit with the addition of the vaccine in these patients with metastatic disease. It may be that vaccination alone is not sufficient and that an effective immunomodulator is required to enhance the immune response. Antibodies to CTLA-4 ??Mechanism of action Malignancy cells produce proteins that are.