title: Feasibility study of adoptive immunotherapy for metastatic lung tumors using peptide-pulsed dendritic cell-activated killer (PDAK) cells.
abstract: We have established a novel culture system to generate effector lymphocytes designated as peptide-pulsed dendritic cell-activated killer (PDAK) cells using cultured dendritic cells (DCs), synthetic peptide, peripheral blood lymphocytes, and interleukin-2 plus immobilized anti-CD3 antibody. A feasibility study of an adoptive immunotherapy trial using PDAK cells was conducted on HLA-A2 and HLA-A24 cancer patients with antigen-positive lung metastasis that was defined by serological analysis or PCR analysis. Eleven patients with lung metastasis participated in the study: 6 with colorectal cancer, 2 with pancreatic cancer, 1 each with breast and lung cancer, and 1 with melanoma. The patients received either Muc-1, CEA, gpl00, Her-2 or SART-3-PDAK cells generated in vitro, intravenously in combination with 350,000 U IL-2 weekly for 9 weeks, together with a planned dose-escalation schedule of three transfers each of 1 x 10(7), 3 x 10(7) and 1 x 10(8) PDAK cells/kg for 6 patients, and with a uniform dose of 3 x 10(7) PDAK cells/kg for the remaining 5 patients. Peptide/HLA-specific cytotoxic activity and TCRVbeta gene usage of PDAK cells were analyzed. All transfers of PDAK cells, which showed peptide/HLA-specific lysis, were well-tolerated in all patients, and adverse effects (elevation of transaminase, fever, and headache) were observed primarily at grade 1, but in no case greater than grade 2. The generation of sufficient cells to treat the patients with 3 x 10(7) PDAK cells/kg was feasible using our culture system, but we were able to generate and administer the dose of 1 x 10(8) PDAK cells/kg in only one patient. One partial response (PR) of lung metastasis occurred in a pancreatic cancer patient who received 3 x 10(7) Muc-1-PDAK cells/kg. The cytolytic units of PDAK cells in this patient appeared to be substantially higher compared to those in PD patients. TCR gene usage analysis on PDAK cells revealed preferential usage of TCRVbeta segments. These results suggest that adoptive immunotherapy using PDAK cells for cancer patients with antigen-positive lung metastasis is safe and feasible, and tumor response should be examined in a future clinical trial
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan. shogo@hiroshima-u.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Ohta
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawabuchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohshita
authors.forename: Riki
authors.initials: R
authors.lastname: Okita
authors.forename: Makoto
authors.initials: M
authors.lastname: Okawaki
authors.forename: Katsuji
authors.initials: K
authors.lastname: Hironaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsuura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Toge
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005240:Feasibility Studies; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D059871:HLA-A24 Antigen; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; D008562:Membrane Glycoproteins; D018396:Mucin-1; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D058951:gp100 Melanoma Antigen; C548637:PMEL protein, human; C416530:SART3 protein, human