Vaccination of melanoma patients with peptide- or tumorlysate-pulsed dendritic cells
Frank O. Nestle1, Selma Alijagic2, Michel Gilliet1, Yuansheng Sun2, Stephan Grabbe3, Reinhard Dummer1, Günter Burg1
& Dirk Schadendorf2
1Department of Dermatology, University of Zurich Medical School,Gloriastrasse 31, 8091 Zurich, Switzerland
2Clinical Cooperation Unit for Dermatooncology (DKFZ) at the Klinikum Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1, 68135 Mannheim, Germany
3Department of Dermatology, University of Münstervon Esmarck Str. 56, 48149 Münster, Germany
Melanoma is the main cause of death in patients with skin cancer1. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified2. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response3. Mouse studies have demonstrated the potent capacity of DCs to induce antitu-mor immunity4−11. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced de-layed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.
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