Analysis of a natural immune response against tumor antigens in a melanomasurvivor: Lessons applicable to clinical trial evaluations

The long-term survival of some patients with metastatic melanoma may be att ributable in part to cellular immune responses to melanoma antigens, Howeve r, little is known about the level of CTL reactivity in vivo that is requir ed for immunological control of tumor progression. In the present report, T -cell responses were evaluated with lymphocytes obtained from tumor-involve d nodes and peripheral blood of a long-term melanoma survivor. Using an ELI SPOT assay, naturally occurring functional T cells, which recognize the pep tide ALLAVGATK (gp100(17-25)) plus two other HLA-A3 restricted peptides, we re detected in a tumor-involved lymph node. The ALLAVGATK-reactive T cells were also evaluated by MHC-tetramers staining and were found to be CD8(+) C D45RO(+) L-selectin(-) CD11a(+), suggesting that they are antigen experienc ed and have a memory phenotype, Unstimulated peripheral blood lymphocytes f rom the same patient demonstrated no detectable T-cell responses; however, a single stimulation with ALLAVGATK peptide in vitro resulted in a dramatic expansion of peptide-reactive CTLs, This patient, with evidence of tumor-r eactive CTLs targeted to several tumor antigens in a tumor-involved lymph n ode and with evidence of a circulating memory T-cell response, has remained disease-free for 6 years, despite prior bulky nodal metastasis, In contras t, three HLA-A3(+) patients with rapidly progressive metastatic melanoma ha d no detectable T-cell response in tumor-involved nodes or peripheral blood lymphocytes, even after peptide stimulation ex vivo. The presented data ar e consistent with a systemic polyvalent immune response against tumor in th is long-term survivor. These data provide an estimate of the level of CTL r esponse that may be associated with protection from tumor recurrence.