Phase I Study in Melanoma Patients of a Vaccine With Peptide-Pulsed Dendritic Cells Generated IN VITRO From CD34+ Hematopoietic Progenitor Cells

Mackensen, A., B. Herbst, J-L. Chen, G. Kohler, C. Noppen, W. Herr, GC. Spagoli, V. Cerundolo, A. Lindemann. 

Dept of Hematology Oncology, Dept of Pathology, Freiburg University Medical Center, Freiburg, Germany.   Inr. Institute of Molecular Medicine, Nuffield Dept of Clinical Medicine, Oxford, UK. Research Division, Dept of Surgery, University of Basel, Basel, Switzerland. Johannes Gutenberg Universitat Mainz, III Medizinische Klinik, Mainz, Germany.    Int. J. Cancer: 86, 385-392 (2000)

 

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-a.

Here, we report on a phase I clinical vaccination trial in melanoma patients using peptide-pulsed DCs. Fourteen HLA-A1+ or HLA-2+ patients received at least 4 i.v. infusions of 5 x 106 to 5 X 107 DCs pulsed with a pool of peptides including either MAGE-I, MAGE-3 (HLA-A1) or Melan-A, gp 100, tyrosinase (HLA-A2), depending on the HLA haplotype. A total of 83 vaccinations were performed.

Clinical side effects were mild and consisted of lowgrade fever (WHO grade 1-11), 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 gp 100-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.