title: Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma.
abstract: The primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-gamma expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.
authors.affiliation: Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800E, Los Angeles, CA 90048, USA. Yuj@cshs.org
authors.forename: John S
authors.initials: JS
authors.lastname: Yu
authors.forename: Gentao
authors.initials: G
authors.lastname: Liu
authors.forename: Han
authors.initials: H
authors.lastname: Ying
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wheeler
mesh_terms: D000328:Adult; D001254:Astrocytoma / Q000276:immunology / Q000628:therapy*; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte