A phase I trial of an HLA-A1 restricted MAGE-3 epitope peptide with incomplete Freund's adjuvant in patients with resected high-risk melanoma.
Cytolytic and helper T cells recognize small peptide fragments of protein antigens that are intracellularly processed and delivered to the cell surface in conjunction with HLA molecules. In mice, peptide vaccines can protect against lethal virus infections and tumor challenges. To test whether epitope peptides derived from a human tumor antigen can induce immune responses in patients, a vaccine was prepared consisting of an HLA-A1-restricted epitope of the antigen MAGE-3 mixed with a pan-class II epitope peptide PADRE and emulsified with incomplete Freund's adjuvant. Eighteen patients with resected stages III and IV melanoma at high risk for relapse were vaccinated subcutaneously with increasing doses of the MAGE-3 vaccine ranging from 100 to 2,000 micrograms per injection four times, each 4 weeks apart. The purpose of the phase I trial was to assess the toxicity, tolerability, and immune responses to the vaccine. The vaccine was not toxic, with only one case of grade III lethargy, and most patients complaining of grade I or II local pain, swelling, and tenderness at the injection sites. Peripheral blood mononuclear cells (PBMC) were collected from most patients prior to and after vaccination and used for assessment of global levels of immunity prevaccination, and to measure immune responses to the MAGE-3 and PADRE peptides prior to and after vaccination. Significant defects in global immunity shown by anergy to DTH skin testing in 7 of 16 patients and decreased proliferation to PHA (phytohemagglutinin) and CASTA, a Candida albicans protein extract, were observed. Seven of nine patients showed an increased response to PADRE after restimulation in vitro. Five of 14 patients at doses from 100 to 2,000 micrograms demonstrated an immune response to MAGE-3 by cytolysis of MAGE-3-specific target cells. Release of gamma interferon by T cells from 8 patients at the 100, 1,000, or 2,000 micrograms dose was measured after vaccination, and only two of eight patients showed an increase indicating augmented antigen-specific immunity. These data suggest that immune responses can be detected against PADRE and MAGE-3 in vaccinated melanoma patients, albeit with a low frequency of effector cells.
Weber
J S
JS
Department of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles 90033, USA.
Hua
F L
FL
Spears
L
L
Marty
V
V
Kuniyoshi
C
C
Celis
E
E
D000951:Antigens, Neoplasm / Q000009:adverse effects / Q000627:therapeutic use*; D018984:Epitopes, T-Lymphocyte / Q000627:therapeutic use; D005260:Female; D005620:Freund's Adjuvant / Q000627:therapeutic use*; D006801:Humans; D016056:Immunodominant Epitopes / Q000627:therapeutic use*; D008055:Lipids; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology / Q000628:therapy*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D008055:Lipids; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; C114843:incomplete Freund's adjuvant; D005620:Freund's Adjuvant