title: Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression.
abstract: Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.
authors.affiliation: Department of Surgery, Section of Pediatric Surgery, Section of General Surgery, the Tumor Immunology and Immunotherapy Program, Ann Arbor, Michigan 48109-0245, USA. jgeiger@umich.edu
authors.forename: J D
authors.initials: JD
authors.lastname: Geiger
authors.forename: R J
authors.initials: RJ
authors.lastname: Hutchinson
authors.forename: L F
authors.initials: LF
authors.lastname: Hohenkirk
authors.forename: E A
authors.initials: EA
authors.lastname: McKenna
authors.forename: G A
authors.initials: GA
authors.lastname: Yanik
authors.forename: J E
authors.initials: JE
authors.lastname: Levine
authors.forename: A E
authors.initials: AE
authors.lastname: Chang
authors.forename: T M
authors.initials: TM
authors.lastname: Braun
authors.forename: J J
authors.initials: JJ
authors.lastname: Mulé
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D007937:Leukapheresis; D008297:Male; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination
chemical_list: D007371:Interferon-gamma; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin