Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generatedin vitro from CD34+ hematopoietic progenitor cells

Abstract

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‐α. 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 × 106 to 5 × 107 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. Int. J. Cancer 86:385–392, 2000. © 2000 Wiley‐Liss, Inc.

Pathways and therapeutic targets in melanoma

“…In a different approach, immature DCs were generated from CD34+ hematopoietic progenitor cells through stimulation with a predefined cytokine cocktail, and matured in vitro by pulsing with a pool of peptides derived from known melanoma antigens [267]. This study reported durable immune responses and perhaps one objective clinical response.…”

Serological detection of cutaneous T-cell lymphoma-associated antigens

“…Most of these have originally been identified in melanoma, but subsequently have been found to be expressed in various other tumors like neuroblastoma (30), gastric carcinoma (31), ovarian tumors (32), and hepatocellular tumors (33). The possible value of these antigens for tumor immunological treatment is currently being investigated (13,34,35).…”

Dendritic cell vaccination for cancer therapy

“…In ongoing immunotherapy protocols, DC are either generated from immature circulating blood precursors or by in vitro culture of monocytes or CD34 progenitor cells. Currently the major sources of DC for immunotherapy are: (i) CD34 cells cultured in complex cytokine cocktails including SCF, IL-3, IL-6, IL-4, GM-CSF (Mackensen et al, 2000b); (ii) monocyte derived DCs cultured in IL-4, GM-CSF (+/7 further maturation stimuli) and (iii) blood derived DC obtained through a modi®ed gradient method (Burch et al, 2000).…”

“…A trial using CD34 derived DC matured with TNF-a, injected i.v. in 14 patients with advanced melanoma showed tumor regression in two patients, DTH reactions in four patients and expansion of peptide speci®c CTL in one patient (Mackensen et al, 2000b). In multiple myeloma patients who have undergone peripheral stem cell rescue following ablative chemotherapy DCs were loaded with myeloma speci®c immunoglobulin idiotypes puri®ed from serum and injected into the patients.…”