Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 63; no. 21; pp. 7497 - 7506
• Main Authors: FREYTAG, Svend O, STRICKER, Hans, JAE HO KIM, PEGG, Jan, PAIELLI, Dell, PRADHAN, Deepak G, PEABODY, James, DEPERALTA-VENTURINA, Mariza, XUEQING XIA, BROWN, Steve, MEI LU
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.2003
• Subjects: Adenovirus; Adenoviruses, Human - genetics; Adenoviruses, Human - physiology; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Combined Modality Therapy; Cytosine Deaminase - biosynthesis; Cytosine Deaminase - genetics; Cytosine Deaminase - metabolism; DNA, Viral - blood; Flucytosine - adverse effects; Flucytosine - pharmacokinetics; Flucytosine - therapeutic use; Ganciclovir - adverse effects; Ganciclovir - analogs & derivatives; Ganciclovir - pharmacokinetics; Ganciclovir - therapeutic use; Gene Expression; Genetic Therapy - adverse effects; Genetic Therapy - methods; Humans; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - therapy; Prostatic Neoplasms - virology; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Simplexvirus - enzymology; Simplexvirus - genetics; Thymidine Kinase - biosynthesis; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Transgenes; Tumors; Virus Replication; High risk; Adenoviridae; Early stage; Malignant tumor; Suicide gene; Radiotherapy; Virus; Phase I trial; Replication; Combined treatment; Gene therapy; Urogenital system; Dose; Prostate
• ISSN: 0008-5472; 1538-7445

The primary study objective was to determine the safety of intraprostatic administration of a replication-competent, oncolytic adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene concomitant with increasing durations of 5-fluorocytosine and valganciclovir prodrug therapy and conventional-dose three-dimensional conformal radiation therapy (3D-CRT) in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Secondary objectives were to determine the persistence of therapeutic transgene expression in the prostate and to examine early posttreatment response. Fifteen patients in five cohorts received a single intraprostatic injection of 10(12) viral particles of the replication-competent Ad5-CD/TKrep adenovirus on day 1. Two days later, patients were administered 5-fluorocytosine and valganciclovir prodrug therapy for 1 (cohorts 1-3), 2 (cohort 4), or 3 (cohort 5) weeks along with 70-74 Gy 3D-CRT. Sextant needle biopsy of the prostate was obtained at 2 (cohort 1), 3 (cohort 2), and 4 (cohort 3) weeks for determination of the persistence of transgene expression. There were no dose-limiting toxicities and no significant treatment-related adverse events. Ninety-four percent of the adverse events observed were mild to moderate and self-limiting. Acute urinary and gastrointestinal toxicities were similar to those expected for conventional-dose 3D-CRT. Therapeutic transgene expression was found to persist in the prostate for up to 3 weeks after the adenovirus injection. As expected for patients receiving definitive radiation therapy, all patients experienced significant declines in prostate-specific antigen (PSA). The mean PSA half-life in patients administered more than 1 week of prodrug therapy was significantly shorter than that of patients receiving prodrugs for only 1 week (0.6 versus 2.0 months; P < 0.02) and markedly shorter than that reported previously for patients treated with conventional-dose 3D-CRT alone (2.4 months). With a median follow-up of only 9 months, 5 of 10 (50%) patients not treated with androgen-deprivation therapy achieved a serum PSA < or = 0.5 ng/ml. The results demonstrate that replication-competent adenovirus-mediated double-suicide gene therapy can be combined safely with conventional-dose 3D-CRT in patients with intermediate- to high-risk prostate cancer. The shorter than expected PSA half-life in patients receiving more than 1 week of prodrug therapy may suggest a possible interaction between the oncolytic adenovirus and/or double-suicide gene therapies and radiation therapy.