title: Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma.
abstract: Taking advantage of homeostatic mechanisms to boost tumor-specific cellular immunity is raising increasing interest in the development of therapeutic strategies in the treatment of melanoma. Here, we have explored the potential of combining homeostatic proliferation, after transient immunosuppression, and antigenic stimulation of Melan-A/Mart-1 specific CD8 T-cells. In an effort to develop protocols that could be readily applicable to the clinic, we have designed a phase I clinical trial, involving lymphodepleting chemotherapy with Busulfan and Fludarabine, reinfusion of Melan-A specific CD8 T-cell containing peripheral blood mononuclear cells (exempt of growth factors), and Melan-A peptide vaccination. Six patients with advanced melanoma were enrolled in this outpatient regimen that demonstrated good feasibility combined with low toxicity. Consistent depletion of lymphocytes with persistent increased CD4/CD8 ratios was induced, although the proportion of circulating CD4 regulatory T-cells remained mostly unchanged. The study of the immune reconstitution period showed a steady recovery of whole T-cell numbers overtime. However, expansion of Melan-A specific CD8 T-cells, as measured in peripheral blood, was mostly inconsistent, accompanied with marginal phenotypic changes, despite vaccination with Melan-A/Mart-1 peptide. On the clinical level, 1 patient presented a partial but objective antitumor response following the beginning of the protocol, even though a direct effect of Busulfan/Fludarabine cannot be completely ruled out. Overall, these data provide further ground for the development of immunotherapeutic approaches to be both effective against melanoma and applicable in clinic.
authors.affiliation: Multidisciplinary Oncology Center, University of Lausanne Hospitals CHUV, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
authors.forename: Verena
authors.initials: V
authors.lastname: Voelter
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Sévérine
authors.initials: S
authors.lastname: Reynard
authors.forename: Camilla
authors.initials: C
authors.lastname: Jandus
authors.forename: Danielle
authors.initials: D
authors.lastname: Gasparini
authors.forename: Danielle
authors.initials: D
authors.lastname: Lienard
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Philippe
authors.initials: P
authors.lastname: Schneider
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Serge
authors.initials: S
authors.lastname: Leyvraz
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002066:Busulfan / Q000494:pharmacology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008212:Lymphocyte Depletion; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit / Q000627:therapeutic use; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D022223:Vaccines, Subunit; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine