Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+) hematopoietic progenitor cells.
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that can be used for vaccination purposes, to induce a specific T-cell response in vivo against melanoma-associated antigens. We have shown that the sequential use of early-acting hematopoietic growth factors, stem cell factor, IL-3 and IL-6, followed by differentiation with IL-4 and granulocyte-macrophage colony-stimulating factor allows the in vitro generation of large numbers of immature DCs from CD34(+) peripheral blood progenitor cells. Maturation to interdigitating DCs could specifically be induced within 24 hr by addition of TNF-alpha. Here, we report on a phase I clinical vaccination trial in melanoma patients using peptide-pulsed DCs. Fourteen HLA-A1(+) or HLA-A2(+) patients received at least 4 i.v. infusions of 5 x 10(6) to 5 x 10(7) DCs pulsed with a pool of peptides including either MAGE-1, MAGE-3 (HLA-A1) or Melan-A, gp100, tyrosinase (HLA-A2), depending on the HLA haplotype. A total of 83 vaccinations were performed. Clinical side effects were mild and consisted of low-grade fever (WHO grade I-II). Clinical and immunological responses consisted of anti-tumor responses in 2 patients, increased melanoma peptide-specific delayed-type hypersensitivity reactions in 4 patients, significant expansion of Melan-A- and gp100-specific cytotoxic T lymphocytes in the peripheral blood lymphocytes of 1 patient after vaccination and development of vitiligo in another HLA-A2(+) patient. Our data indicate that the vaccination of peptide-pulsed DCs is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects.
Mackensen
A
A
Department of Hematology/Oncology, Freiburg University Medical Center, Freiburg, Germany. andreas.mackensen@klinik.uni-regensburg.de
Herbst
B
B
Chen
J L
JL
Köhler
G
G
Noppen
C
C
Herr
W
W
Spagnoli
G C
GC
Cerundolo
V
V
Lindemann
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D010455:Peptides / Q000276:immunology; D010865:Pilot Projects
D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D010455:Peptides