期刊
JOURNAL OF IMMUNOTHERAPY
卷 27, 期 1, 页码 36-47出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00002371-200401000-00004
关键词
human antigen/peptide/epitope; vaccination; tumor immunity; T lymphocytes; differentiation
资金
- NCI NIH HHS [Z01 SC003811-31] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [Z01SC003800, Z01SC003811] Funding Source: NIH RePORTER
Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8(+) T cells (4.8% to 38.1%) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8(+) T cells from an early effector to an effector memory (CD27(-) CD28(-) CD62L(-) CD45RO(+)) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8(+) T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8(+) T lymphocytes.
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