Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy.

Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24. DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer. An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group. All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.

Lam JT ，Kanerva A ，Bauerschmitz GJ ，Takayama K ，Suzuki K ，Yamamoto M ，Bhoola SM ，Liu B ，Wang M ，Barnes MN ，Alvarez RD ，Siegal GP ，Curiel DT ，Hemminki A ... -  《JOURNAL OF GENE MEDICINE》

A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer.

Rein DT ，Breidenbach M ，Kirby TO ，Han T ，Siegal GP ，Bauerschmitz GJ ，Wang M ，Nettelbeck DM ，Tsuruta Y ，Yamamoto M ，Dall P ，Hemminki A ，Curiel DT ... -  《CLINICAL CANCER RESEARCH》

A novel ex vivo model system for evaluation of conditionally replicative adenoviruses therapeutic efficacy and toxicity.

Kirby TO ，Rivera A ，Rein D ，Wang M ，Ulasov I ，Breidenbach M ，Kataram M ，Contreras JL ，Krumdieck C ，Yamamoto M ，Rots MG ，Haisma HJ ，Alvarez RD ，Mahasreshti PJ ，Curiel DT ... -  《CLINICAL CANCER RESEARCH》

A cyclooxygenase-2 promoter-based conditionally replicating adenovirus with enhanced infectivity for treatment of ovarian adenocarcinoma.

Kanerva A ，Bauerschmitz GJ ，Yamamoto M ，Lam JT ，Alvarez RD ，Siegal GP ，Curiel DT ，Hemminki A ... -  《-》

Treatment of chemotherapy resistant ovarian cancer with a MDR1 targeted oncolytic adenovirus.

Multidrug resistance gene 1 (MDR1) mediated resistance to chemotherapeutic agents is a major obstacle for the therapy of various cancer types. The use of conditionally replicating adenoviruses (CRAds) is dependent on molecular differences between tumor cells and non tumor cells. Transcriptional targeting of CRAd replication is an effective way to control replication regulation. The aim of this study was to evaluate the effect of a MDR1 targeted fiber-modified CRAd against chemotherapy resistant ovarian cancer. MDR1 expression was evaluated in chemotherapy naïve and pretreated ovarian cancer cells and various control cells. We constructed 2 variants of a fiber-modified CRAd, Ad5/3MDR1E1 and Ad5/3MDR1E1∆24 containing the MDR1 promoter to control viral replication via the E1A gene. The MDR promoter activity and cell killing efficacy were evaluated in vitro. Orthotopic murine models of peritoneally disseminated ovarian cancer were utilized to evaluate the preclinical efficacy of MDR targeted CRAds in vivo. To evaluate the liver toxicity of MDR1 targeted CRAds, we compared Ad5/3MDR1E1 with Ad5/3∆24, a CRAd that replicates in cancer cells inactive in the Rb/p16 pathway by use of an in vivo hepatotoxicity model. We demonstrate efficient oncolysis of Ad5/3MDR1E1 in both chemotherapy resistant ovarian cancer cell lines and in primary tumor cells from pretreated patients as well as therapeutic efficacy in an orthotopic mouse model. Ad5/3MDR1E1 demonstrated significantly decreased liver toxicity compared to other 5/3-fiber modified control vectors examined. In summary, Ad5/3MDR1E1 is an efficient and safe gene therapy approach for specific targeting of chemotherapy resistant cancer cells.

Rein DT ，Volkmer A ，Beyer IM ，Curiel DT ，Janni W ，Dragoi A ，Hess AP ，Maass N ，Baldus SE ，Bauerschmitz G ，Breidenbach M ... -  《-》