After vaccination of melanoma patients with MAGE antigens, we observed that even in the few patients showing tumor regression, the frequency of anti-vaccine T cells in the blood was often either undetectable or <10−5 of CD8 T cells. This frequency being arguably too low for these cells to be sole effectors of rejection, we reexamined the contribution of T cells recognizing other tumor antigens. The presence of such antitumor T cells in melanoma patients has been widely reported. To begin assessing their contribution to vaccine-induced rejection, we evaluated their blood frequency in five vaccinated patients. The antitumor cytotoxic T lymphocyte (CTL) precursors ranged from 10−4 to 3 × 10−3, which is 10–10,000 times higher than the anti-vaccine CTL in the same patient. High frequencies were also observed before vaccination. In a patient showing nearly complete regression after vaccination with a MAGE-3 antigen, we observed a remarkably focused antitumoral response. A majority of CTL precursors (CTLp's) recognized antigens encoded by MAGE-C2, another cancer-germline gene. Others recognized gp100 antigens. CTLp's recognizing MAGE-C2 and gp100 antigens were already present before vaccination, but new clonotypes appeared afterwards. These results suggest that a spontaneous antitumor T cell response, which has become ineffective, can be reawakened by vaccination and contribute to tumor rejection. This notion is reinforced by the frequencies of anti-vaccine and antitumor CTLs observed inside metastases, as presented by Lurquin et al. (Lurquin, C., B. Lethé, V. Corbière, I. Théate, N. van Baren, P.G. Coulie, and T. Boon. 2004. J. Exp. Med. 201:249–257).

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We have pursued our analysis of a melanoma patient who showed almost complete tumor regression following vaccination with MAGE-A1 and MAGE-A3 antigens. We previously described high frequencies of tumor-specific CTL precursors in blood samples collected after but also before vaccination. A set of CTL clones were derived that recognized antigens different from those of the vaccine. Two of these antigens were peptides encoded by another MAGE gene, MAGE-C2. Here we describe the antigen recognized by another tumor-specific CTL clone. It proved to be a third antigenic peptide encoded by gene MAGE-C2, ASSTLYLVF. It is presented by HLA-B57 molecules and proteasome-dependent. Tumor cells exposed to interferon-gamma (IFN-c) were better recognized by the anti-MAGE-C2 42-50 CTL clone. This mainly resulted from a better processing of the peptide by the immunoproteasome as compared to the standard proteasome. Mass spectrometric analyses showed that the latter destroyed the antigenic peptide by cleaving between two internal hydrophobic residues. Despite its higher ''chymotryptic-like'' (posthydrophobic) activity, the immunoproteasome did not cleave at this position, in line with the suggestion that hydrophobic residues immediately downstream from a cleavage site impair cleavage by the immunoproteasome. We previously reported that one of the other MAGE-C2 peptides recognized by CTL from this patient was also better processed by the immunoproteasome. Together, these results support the notion that the tumor regression of this patient was mediated by an antitumor response shaped by IFN-c and dominated by CTL directed against peptides that are better produced by the immunoproteasome, such as the MAGE-C2 peptides.The identification of antigens recognized on human tumors by autologous T lymphocytes has opened new possibilities for cancer immunotherapy. One of these was the use of defined tumor-specific antigens to vaccinate melanoma patients with measurable metastatic disease.1 While regression of melanoma metastases was observed in several vaccinated patients, without significant toxicity, it occurred only in a minority of patients. For antigen MAGE-3.A1, i.e., peptide MAGE-A3 168-176 encoded by gene MAGE-A3 and presented by HLA-A1, 125 patients were evaluable for tumor response following vaccination either with the antigenic peptide administered alone or with adjuvant, or with a recombinant MAGE-A3 protein with or without adjuvant, or with a recombinant canarypox virus of the ALVAC type encoding the MAGE-3.A1 antigen, or with dendritic cells pulsed with the peptide.2-5 A complete tumor response was observed in 3 patients, a partial response in 5, and a mixed response in 20. Other groups reported similar clinical efficacies for vaccinations with other tumor antigens. [6][7][8] To understand why vaccination is followed by tumor regression in some patients but not in others, we tried first to understand the mechanisms that lead to tumor regression. Our approach was to analyze in detail the antitumor immune response of a limited numbe...

Liver transplantation can be performed safely in children with Alagille syndrome, even in the presence of elevated right ventricular pressure.