title: Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas.
abstract: OBJECTIVE
  To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity.
  
  
  METHODS
  Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10(6) to 50 x 10(6) cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals.
  
  
  RESULTS
  Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment.
  
  
  CONCLUSIONS
  Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.
authors.affiliation: Division of Hepatology and Gene Therapy, Department of Radiology, Clínica Universitaria/School of Medicine, University of Navarra, c/Irunlarrea, s/n, 31008 Pamplona, Spain. gmazzolini@unav.es
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Bruno
authors.initials: B
authors.lastname: Sangro
authors.forename: Esperanza
authors.initials: E
authors.lastname: Feijoó
authors.forename: Juan
authors.initials: J
authors.lastname: Ruiz
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito
authors.forename: Iñigo
authors.initials: I
authors.lastname: Tirapu
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.forename: Josu
authors.initials: J
authors.lastname: Sola
authors.forename: Maite
authors.initials: M
authors.lastname: Herraiz
authors.forename: Felipe
authors.initials: F
authors.lastname: Lucena
authors.forename: Cristina
authors.initials: C
authors.lastname: Olagüe
authors.forename: José
authors.initials: J
authors.lastname: Subtil
authors.forename: Jorge
authors.initials: J
authors.lastname: Quiroga
authors.forename: Ignacio
authors.initials: I
authors.lastname: Herrero
authors.forename: Belén
authors.initials: B
authors.lastname: Sádaba
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bendandi
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002277:Carcinoma / Q000556:secondary* / Q000628:therapy; D015331:Cohort Studies; D003713:Dendritic Cells / Q000276:immunology*; D005240:Feasibility Studies; D005260:Female; D005334:Fever / Q000209:etiology; D005770:Gastrointestinal Neoplasms / Q000556:secondary* / Q000628:therapy; D006801:Humans; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012074:Remission Induction; D012449:Safety; D023822:Tissue Engineering; D014162:Transfection
chemical_list: D015850:Interleukin-6; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma