Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but doesnot lead to tumor regression

Although in vitro sensitization assays have shown increased melanoma Ag (MA )-specific CTL reactivity after vaccination with MA peptides, clinical resp onses have been uncommon, This paradox questions whether data obtained from the in vitro stimulation and expansion of T cells lead to an overestimatio n of the immune response to vaccines, Using HLA/peptide tetramer (tHLA), we enumerated MA-specific T cell precursor frequency (TCPF) directly in PBMC from 23 melanoma patients vaccinated with gp100:209-217(210M) (g209-2M) pep tide, Vaccine-specific TCPF was higher in postvaccination PBMC from seven o f seven patients treated with peptide alone and four of five patients treat ed with peptide plus IL-12 (range of postvaccination TCPF, 0.2-2.4% and 0.2 -2.5%, respectively), The increased TCPF correlated with enhanced susceptib ility to in vitro stimulation with the relevant epitope, Paradoxically, no increase in postvaccination TCPF was observed in most patients who had been concomitantly treated with IL-2 (1 of 11 patients; range of postvaccinatio n TCPF, 0.02-1.0%), a combination associated with enhanced rates of tumor r egression. The lack of increase in TCPF seen in these patients corresponded to inability to elicit expansion of vaccine-specific T cells in culture, T his study shows that a peptide-based vaccine can effectively generate a qua ntifiable T cell-specific immune response in the PBMC of cancer patients, t hough such a response does not associate with a clinically evident regressi on of metastatic melanoma.