Comparing immunogenicities of tumor-specific antigens administered as therapeutic vaccines in metastatic melanoma patients

Abstract

3003 Background: Therapeutic vaccination of metastatic melanoma patients with detectable disease is followed by some tumor regression in only about 10% of the patients, with no clear difference observed between studies carried out with various tumor-specific antigens and vaccination modalities. For antigenic peptide MAGE-A3168–176, presented by HLA-A1 molecules and administered as peptide alone or recombinant ALVAC poxvirus, anti-vaccine T lymphocyte (CTL) responses have been observed in no progressor patient and in only half of the regressors, suggesting a poor immunogenicity of these vaccines. Methods and Results: We compiled anti-vaccine CTL responses measured in the blood of 202 metastatic melanoma patients vaccinated with various associations of 10 different tumor antigens administered as peptides, alone or with adjuvant, recombinant ALVAC poxvirus, or peptide-pulsed dendritic cells. Blood lymphocytes collected before and after vaccination were all analyzed with the same method involving in vitro restimulation in limiting dilution condition followed by labeling with tetramers for each antigen. A CTL response was deemed to have occurred if the CTL frequency increased by at least 10 times, and if the pre-vaccination frequency was lower than 2 x 10-6 of the CD8 cells. No responses were detected against peptides MAGE- A4230–239 (0/26) and MAGE-C2336–344 (0/22). Some were observed against MAGE-A3168–176 (11/81), MAGE-A1278–286 (2/22), MAGE-A3112–120 (2/55), and MAGE-A10254–262 (2/35). Responses were frequently found against NY-ESO-1157–165 (10/19), GnTVVLPDVFIRC (18/73), gp100209–217 (21/33), or Tyrosinase369–377 (11/59). For the latter four antigens, there was no correlation between the occurrence of CTL responses and that of tumor regressions. Neither did we find a correlation between the CTL responses and the expression of the antigen-encoding genes in pre- vaccination tumor samples. Conclusions: These results suggest that some of the antigenic peptides that are commonly used in melanoma vaccines are more immunogenic than others but do not induce more tumor regressions. Therefore, inducing strong CTL responses against these immunogenic peptides is probably not the most appropriate endpoint of future vaccine trials. No significant financial relationships to disclose.