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Published on: July 30, 2018
In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus
Akseli Hemminki1, Kurt R Zinn, Bin Liu
1Division of Human Gene Therapy and Gene Therapy Center, Department of Medicine, University of Alabama at Birmingham, 35294-3300, USA. akseli@uab.edu
Background:
Adenovirus-based gene therapy is a promising approach to treat advanced cancers that are resistant to other treatments. However, many primary cells lack the requisite coxsackie-adenovirus receptor (CAR), limiting the in vivo efficacy of gene therapy. Recently, a modified adenovirus that is not dependent on CAR expression for infectivity was developed. We used noninvasive imaging to investigate the in vivo antitumor efficacy of gene therapy using this adenovirus in an animal model of ovarian cancer.
Methods:
The adenoviral vectors RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes simplex virus thymidine kinase (TK) for molecular chemotherapy and the human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were established from highly aggressive SKOV3.ip1 cells in immune-deficient mice. Adenoviral constructs were infected intratumorally or intraperitoneally once a day for 3 days. Control mice received three injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector that includes a luciferase marker gene. The somatostatin analogue (99m)Tc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that was injected into subcutaneous tumors. For mice with peritoneal tumors, survival was compared among the different treatment groups using Kaplan-Meier analysis with the log-rank statistic. All statistical tests were two-sided.
Results:
Tumor-associated RGDTKSSTR could be detected 15 days after introduction of the vector. In the subcutaneous model, tumors injected with RGDTKSSTR were statistically significantly smaller than those injected with AdTKSSTR (P<.001). In the intraperitoneal model, mice treated with RGDTKSSTR lived longer (survival at day 45 = 63.6%; 95% confidence interval [CI] = 35.2% to 92.0%) than those treated with AdTKSSTR (survival at day 45 = 0%) or Ad5Luc1 (survival at day 45 = 18.1%; 95% CI = 0.0% to 41.0%).
Discussion:
RGDTKSSTR shows antitumor efficacy against ovarian cancer in vivo in animal models. The virus can be imaged noninvasively and may have the potential to be a useful agent for treating ovarian cancer.
Insights
A novel CAR-independent adenovirus (RGDTKSSTR) demonstrated significant antitumor effects in ovarian cancer models. This gene therapy approach, visualized through noninvasive imaging, offers potential for treating resistant ovarian cancers.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Cancer research
Background:
- Adenovirus gene therapy shows promise for advanced cancers.
- Limited efficacy due to low coxsackie-adenovirus receptor (CAR) expression in cancer cells.
- Development of CAR-independent adenoviruses offers a potential solution.
Purpose of the Study:
- To investigate the in vivo antitumor efficacy of a CAR-independent adenovirus (RGDTKSSTR) in an ovarian cancer model.
- To evaluate the potential of noninvasive imaging for tracking gene therapy delivery and efficacy.
Main Methods:
- Utilized CAR-independent (RGDTKSSTR) and CAR-dependent (AdTKSSTR) adenoviral vectors expressing TK and SSTR.
- Established subcutaneous and peritoneal human ovarian cancer xenografts in immune-deficient mice.
- Administered vectors intratumorally or intraperitoneally and monitored using noninvasive nuclear imaging.
Main Results:
- RGDTKSSTR demonstrated significant tumor reduction in subcutaneous models (P<.001).
- Mice treated with RGDTKSSTR showed improved survival in peritoneal models (45-day survival: 63.6%).
- CAR-dependent vectors resulted in significantly less tumor reduction and survival.
Conclusions:
- RGDTKSSTR exhibits potent antitumor efficacy against ovarian cancer in vivo.
- Noninvasive imaging facilitates tracking of the therapeutic adenovirus.
- This CAR-independent adenovirus holds potential as a novel ovarian cancer treatment.
