A phase I/II clinical trial in localized prostate cancer of an adenovirus expressing nitroreductase with CB1954 [correction of CB1984].
We report a phase I/II clinical trial in prostate cancer (PCa) using direct intraprostatic injection of a replication defective adenovirus vector (CTL102) encoding bacterial nitroreductase (NTR) in conjunction with systemic prodrug CB1954. One group of patients with localized PCa scheduled for radical prostatectomy received virus alone, prior to surgery, in a dose escalation to establish safety, tolerability, and NTR expression. A second group with local failure following primary treatment received virus plus prodrug to establish safety and tolerability. Based on acceptable safety data and indications of prostate-specific antigen (PSA) responses, an extended cohort received virus at a single dose level plus prodrug. The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Immunohistochemistry of resected prostate demonstrated NTR staining in tumor and glandular epithelium at all dose levels [5 x 10(10)-1 x 10(12) virus particles (vp)]. A total of 19 patients received virus plus prodrug and 14 of these had a repeat treatment; minimal toxicity was observed and there was preliminary evidence of change in PSA kinetics, with an increase in the time to 10% PSA progression in 6 out of 18 patients at 6 months.
Patel
Prashant
P
CR UK Institute for Cancer Studies, University of Birmingham, UK.
Young
J Graham
JG
Mautner
Vivien
V
Ashdown
Daniel
D
Bonney
Sarah
S
Pineda
Robert G
RG
Collins
Stuart I
SI
Searle
Peter F
PF
Hull
Diana
D
Peers
Elizabeth
E
Chester
John
J
Wallace
D Michael
DM
Doherty
Alan
A
Leung
Hing
H
Young
Lawrence S
LS
James
Nicholas D
ND
D000256:Adenoviridae / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001388:Aziridines / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009601:Nitroreductases / Q000235:genetics / Q000502:physiology*; D011355:Prodrugs / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000628:therapy*
D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; D009601:Nitroreductases