Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma.
Dendritic cells (DCs) are considered to be promising adjuvants for inducing immunity to cancer. We used mature, monocyte-derived DCs to elicit resistance to malignant melanoma. The DCs were pulsed with Mage-3A1 tumor peptide and a recall antigen, tetanus toxoid or tuberculin. 11 far advanced stage IV melanoma patients, who were progressive despite standard chemotherapy, received five DC vaccinations at 14-d intervals. The first three vaccinations were administered into the skin, 3 x 10(6) DCs each subcutaneously and intradermally, followed by two intravenous injections of 6 x 10(6) and 12 x 10(6) DCs, respectively. Only minor (less than or equal to grade II) side effects were observed. Immunity to the recall antigen was boosted. Significant expansions of Mage-3A1-specific CD8(+) cytotoxic T lymphocyte (CTL) precursors were induced in 8/11 patients. Curiously, these immune responses often declined after the intravenous vaccinations. Regressions of individual metastases (skin, lymph node, lung, and liver) were evident in 6/11 patients. Resolution of skin metastases in two of the patients was accompanied by erythema and CD8(+) T cell infiltration, whereas nonregressing lesions lacked CD8(+) T cells as well as Mage-3 mRNA expression. This study proves the principle that DC "vaccines" can frequently expand tumor-specific CTLs and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8(+) CTL-tumor cell interaction in situ as well as escape by lack of tumor antigen expression.
Thurner
B
B
Department of Dermatology, University of Erlangen-Nuremberg, D-91052 Erlangen, Germany.
Haendle
I
I
Röder
C
C
Dieckmann
D
D
Keikavoussi
P
P
Jonuleit
H
H
Bender
A
A
Maczek
C
C
Schreiner
D
D
von den Driesch
P
P
Bröcker
E B
EB
Steinman
R M
RM
Enk
A
A
Kämpgen
E
E
Schuler
G
G
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000276:immunology*; D009367:Neoplasm Staging; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology; D014373:Tuberculin / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D013745:Tetanus Toxoid; D014373:Tuberculin