Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer.
Adenovirus-mediated suicide gene therapy may hold promise in the treatment of human cancer. We have developed a novel approach that utilizes a lytic, replication-competent adenovirus (Ad5-CD/TKrep) to deliver a cytosine deaminase/herpes simplex virus-1 thymidine kinase fusion gene to tumors. The cytosine deaminase and herpes simplex virus-1 thymidine kinase suicide genes render malignant cells sensitive to specific pharmacological agents and, importantly, sensitize them to radiation. The Phase I study described here represents the first gene therapy trial in which a replication-competent virus was used to deliver a therapeutic gene to humans. The indication is local recurrence of prostate cancer after definitive radiation therapy. An escalating dose (10(10), 10(11), and 10(12) viral particles) of the Ad5-CD/TKrep virus was injected intraprostatically under transrectal ultrasound guidance into 16 patients in four cohorts. Two days later, patients were given 5-fluorocytosine and ganciclovir prodrug therapy for 1 (cohorts 1-3) or 2 (cohort 4) weeks. There were no dose-limiting toxicities, and the maximum tolerated dose of the Ad5-CD/TKrep vector was not defined. Ninety-four percent of the adverse events observed were mild or moderate (grade 1/2) in nature. Seven of 16 (44%) patients demonstrated a >or=25% decrease in serum prostate-specific antigen, and 3 of 16 (19%) patients demonstrated a >or=50% decrease in serum prostate-specific antigen. Transgene expression and tumor destruction at the injection site were confirmed by sextant needle biopsy of the prostate at 2 weeks. Two patients were negative for adenocarcinoma at 1 year follow-up. Although Ad5-CD/TKrep viral DNA could be detected in blood as far out as day 76, no infectious adenovirus was detected in patient serum or urine. Together, the results demonstrate that intraprostatic administration of the replication-competent Ad5-CD/TKrep virus followed by 2 weeks of 5-fluorocytosine and ganciclovir prodrug therapy can be safely applied to humans and is showing signs of biological activity.
Freytag
Svend O
SO
Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan 48202-3450, USA. sfreyta1@hfhs.org
Khil
Mark
M
Stricker
Hans
H
Peabody
James
J
Menon
Mani
M
DePeralta-Venturina
Mariza
M
Nafziger
Daniel
D
Pegg
Jan
J
Paielli
Dell
D
Brown
Steve
S
Barton
Ken
K
Lu
Mei
M
Aguilar-Cordova
Estuardo
E
Kim
Jae Ho
JH
D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D043525:Cytosine Deaminase; D004279:DNA, Viral / Q000097:blood; D005437:Flucytosine / Q000493:pharmacokinetics / Q000627:therapeutic use; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000627:therapeutic use; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000235:genetics / Q000628:therapy*; D009700:Nucleoside Deaminases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D017201:Virus Shedding
D004279:DNA, Viral; D011355:Prodrugs; D005437:Flucytosine; D013937:Thymidine Kinase; D017430:Prostate-Specific Antigen; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D015774:Ganciclovir