Clinical trials performed vaccinating cancer patients with class I binding peptides derived from a variety of tumor antigens have demonstrated that patients can be immunized to boost immunity to self-tumor antigens. Peptide-based vaccines offer an excellent model for assessing the ability to immunize by measuring immunity generated with assays that can specifically measure class I T-cell responses. Lee et al. (13) used MHC tetramer flow cytometry to evaluate in vivo response to vaccination with gp100209_217 and tyrosinase368-376 peptides in 44 HLA-A2 patients with advanced-stage melanoma. Tetramer assays performed before, during, and following the period of vaccination demonstrated appearance of gp100-specific T cells as early as 4 wk, i.e., after two vaccinations. At 18 wk at least 20% of CD8+ T cells were specific for gp100209-217 in four of six patients. Overall, 37 of 42 patients developed an immune response to gp100209-217 following vaccination as measured by MHC tetramer assay. Conversely, only minimal increases were seen in tyrosinase368-376-specific T cells on tetramer assay following vaccination. Monitoring immunity to specific peptides will also allow information to be collected concerning the evolution of the immune response after active immunization. Speiser and colleagues (14) characterized Melan-A-specific cells in melanoma patients as compared to volunteer controls. The cell-surface receptors HLA-DR, CD45RA, CCR7, CD28, and 2B4 were assessed to evaluate differential expression in response to in vitro antigen stimulation. In volunteer donors, Melan-A-stimulated T cells manifested a phe-notype characteristic of naïve cells. In melanoma patients, Melan-A-stimulated T cells expressed a partially activated phenotype and Melan-A-stimulated tumor-infiltrating lymphocytes expressed the phenotype of an effector cell. Following vaccination with Melan-A peptides, patients with advanced-stage melanoma demonstrated increased frequencies of Melan-A-specific T cells, and transition of cells from a naïve state to a more activated state via upregulation of HLA-DR and 2B4 and downregulation of CD45RA and CCR7. ELIspot assays of these cells were predominantly negative, consistent with incomplete transformation of T cells from naïve to effector phenotypes.
Most importantly, these early studies of class I specific peptide-based vaccines are beginning to show evidence of clinical responses. In a recent clinical trial performed by Scheibenbogen et al. (15), two patients with stage IV melanoma received immunization with tyrosinase peptides (tyrosinase368-376in Patient 1, and tyrosinase206-214in Patient 2). Patient 1 had experienced nine relapses over the 3-yr period before vaccination, had a nodal recurrence occurred following the sixth vaccination, but then remained relapse free for 30 mo. Patient 2 had experienced 12 relapses in the 3 yr prior to vaccination, then following vaccination remained free of disease for 27 mo. At 27 mo a visceral recurrence was resected, and Patient 2 remained disease-free for an additional 8 mo at the time of the report. This study highlights the prolonged relapse-free survival peptide-specific tumor vaccines may be able to induce in patients with advanced-stage malignancy.
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