Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas.
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.
Mazzolini
Guillermo
G
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
Alfaro
Carlos
C
Sangro
Bruno
B
Feijoó
Esperanza
E
Ruiz
Juan
J
Benito
Alberto
A
Tirapu
Iñigo
I
Arina
Ainhoa
A
Sola
Josu
J
Herraiz
Maite
M
Lucena
Felipe
F
Olagüe
Cristina
C
Subtil
José
J
Quiroga
Jorge
J
Herrero
Ignacio
I
Sádaba
Belén
B
Bendandi
Maurizio
M
Qian
Cheng
C
Prieto
Jesús
J
Melero
Ignacio
I
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
D015850:Interleukin-6; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma