Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors.
OBJECTIVE
To evaluate the feasibility and safety of intratumoral injection of an adenoviral vector encoding human interleukin-12 genes (Ad.IL-12) and secondarily, its biologic effect for the treatment of advanced digestive tumors.


METHODS
Ad.IL-12 was administered in doses ranging from 2.5 x 10(10) to 3 x 10(12) viral particles, to seven cohorts of patients with advanced pancreatic, colorectal, or primary liver malignancies. Patients were thoroughly assessed for toxicity, and antitumor response was evaluated by imaging techniques, tumor biopsy, and hypersensitivity skin tests. Patients with stable disease and no serious adverse reactions were allowed to receive up to 3 monthly doses of Ad.IL-12.


RESULTS
Twenty-one patients (nine with primary liver, five with colorectal, and seven with pancreatic cancers) received a total of 44 injections. Ad.IL-12 was well tolerated, and dose-limiting toxicity was not reached. Frequent but transient adverse reactions, including fever, malaise, sweating, and lymphopenia, seemed to be related to vector injection rather than to transgene expression. No cumulative toxicity was observed. In four of 10 assessable patients, a significant increase in tumor infiltration by effector immune cells was apparent. A partial objective remission of the injected tumor mass was observed in a patient with hepatocellular carcinoma. Stable disease was observed in 29% of patients, mainly those with primary liver cancer.


CONCLUSIONS
Intratumoral injection of up to 3 x 10(12) viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.
Sangro
Bruno
B
Liver Unit, Division of Gene Therapy, Department of Internal Medicine, Clinica Universitaria, University of Navarre, Ap. 4209 Pamplona 31080, Spain. bsangro@unav.es
Mazzolini
Guillermo
G
Ruiz
Juan
J
Herraiz
Maite
M
Quiroga
Jorge
J
Herrero
Ignacio
I
Benito
Alberto
A
Larrache
Javier
J
Pueyo
Jesus
J
Subtil
Jose Carlos
JC
Olagüe
Cristina
C
Sola
Josu
J
Sádaba
Belén
B
Lacasa
Carlos
C
Melero
Ignacio
I
Qian
Cheng
C
Prieto
Jesus
J
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000628:therapy; D004067:Digestive System Neoplasms / Q000628:therapy*; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000628:therapy
D018664:Interleukin-12