Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients.
OBJECTIVE
To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients.


METHODS
Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays.


RESULTS
The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation.


CONCLUSIONS
We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.
Luiten
Rosalie M
RM
Clinical Immunotherapy, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Kueter
Esther W M
EW
Mooi
Wolter
W
Gallee
Maarten P W
MP
Rankin
Elaine M
EM
Gerritsen
Winald R
WR
Clift
Shirley M
SM
Nooijen
Willem J
WJ
Weder
Pauline
P
van de Kasteele
Willeke F
WF
Sein
Johan
J
van den Berk
Paul C M
PC
Nieweg
Omgo E
OE
Berns
Anton M
AM
Spits
Hergen
H
de Gast
Gijsbert C
GC
D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014820:Vitiligo / Q000209:etiology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D016178:Granulocyte-Macrophage Colony-Stimulating Factor