Ad5/3-9HIF-Δ24-VEGFR-1-Ig, an infectivity enhanced, dual-targeted and antiangiogenic oncolytic adenovirus for kidney cancer treatment (original) (raw)
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Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses
Molecular Cancer Therapeutics, 2007
Renal cancer is a common and deadly disease that lacks curative treatments when metastatic. Here, we have used oncolytic adenoviruses, a promising developmental approach whose safety has recently been validated in clinical trials. Although preliminary clinical efficacy data exist for selected tumor types, potency has generally been less than impressive. One important reason may be that expression of the primary receptor, coxsackie-adenovirus receptor, is often low on many or most advanced tumors, although not evaluated in detail with renal cancer. Here, we tested if fluorescence-assisted cell sorting could be used to predict efficacy of a panel of infectivity-enhanced capsid-modified marker gene expressing adenoviruses in renal cancer cell lines, clinical specimens, and subcutaneous and orthotopic murine models of peritoneally metastatic renal cell cancer. The respective selectively oncolytic adenoviruses were tested for killing of tumor cells in these models, and biodistribution after locoregional delivery was evaluated. In vivo replication was analyzed with noninvasive imaging. Ad5/3-#24, Ad5-#24RGD, and Ad5.pK7-#24 significantly increased survival of mice compared with mock or wild-type virus and 50% of Ad5/3-#24 treated mice were alive at 320 days. Because renal tumors are often highly vascularized, we investigated if results could be further improved by adding bevacizumab, a humanized antivascular endothelial growth factor antibody. The combination was well tolerated but did not improve survival, suggesting that the agents may be best used in sequence instead of together. These results set the stage for clinical testing of oncolytic adenoviruses for treatment of metastatic renal cancer currently lacking other treatment options. [Mol Cancer
Targeting of adenovirus to human renal cell carcinoma cells
Urology, 2003
ObjectivesThe use of recombinant adenoviruses in cancer gene therapy is limited by the widespread expression of the coxsackievirus and adenovirus receptor on normal human cells. Targeting adenoviral vectors to renal cell carcinoma (RCC) cells may improve their potential in cancer gene therapy of patients with metastatic RCC. The G250 protein, also known as the carbonic anhydrase IX protein, is membranously
Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches
Cancer therapy using oncolytic viruses is an emerging area, in which viruses are engineered to selectively propagate in tumor tissues without affecting healthy cells. Because of the advantages that adenoviruses (Ads) have over other viruses, they are more considered. To achieve tumor selectivity, two main modifications on Ads genome have been applied: small deletions and insertion of tissue‐ or tumor‐specific promoters. Despite oncolytic adenoviruses ability in tumor cell lysis and immune responses stimulation, to further increase their antitumor effects, genomic modifications have been carried out including insertion of checkpoint inhibitors and antigenic or immunostimulatory molecules into the adenovirus genome and combination with dendritic cells and chemotherapeutic agents. This study reviews oncolytic adenoviruses structures, their antitumor efficacy in combination with other therapeutic strategies, and finally challenges around this treatment approach. 1. Cancer therapy using oncolytic viruses is an emerging area, in which viruses are engineered to selectively propagate in tumor tissues without affecting healthy cells. 2. Despite oncolytic adenoviruses ability in tumor cell lysis and immune responses stimulation, some combinations have been applied to increase their antitumor effects. Cancer therapy using oncolytic viruses is an emerging area, in which viruses are engineered to selectively propagate in tumor tissues without affecting healthy cells. Despite oncolytic adenoviruses ability in tumor cell lysis and immune responses stimulation, some combinations have been applied to increase their antitumor effects.
Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications
Viruses, 2015
Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, c...
Oncolytic adenoviruses in anticancer therapy: Current status and prospects
Molecular Biology, 2012
Lytic virus infection results in production of a virus progeny and lysis of the infected cell. Tumor cells are usually more sensitive to virus infection. Studies indicate that viral oncolysis provides a promising alternative approach to cancer therapy. The ability of viruses to selectively kill cancer cells is long known, but construction of virus variants with an improved therapeutic potential was impossible until recent advances in virus and cell molecular biology and the development of modern methods for directed modification of viruses. Adenoviruses are one of the best studied models of oncolytic viruses. These DNA viruses are conve nient for genetic manipulation and show minimal pathogenicity. The review summarizes the data on the directions and approaches to generation of highly efficient variants of oncolytic adenoviruses. The approaches include introduction of directed genetic modifications into the virus genome, accelerated selec tion of oncolytic virus variants following treatment with mutagens, the use of adenoviruses as vectors to intro duce therapeutic gene products, optimization of viral delivery systems, minimization of the negative effects from the host immune system, etc. The dynamic development of studies in the field holds promise that many variants of oncolytic adenoviruses will find clinical application in the nearest future.
Role of Adenoviruses in Cancer Therapy
Frontiers in Oncology
Cancer is one of the leading causes of death in the world, which is the second after heart diseases. Adenoviruses (Ads) have become the promise of new therapeutic strategy for cancer treatment. The objective of this review is to discuss current advances in the applications of adenoviral vectors in cancer therapy. Adenoviral vectors can be engineered in different ways so as to change the tumor microenvironment from cold tumor to hot tumor, including; 1. by modifying Ads to deliver transgenes that codes for tumor suppressor gene (p53) and other proteins whose expression result in cell cycle arrest 2. Ads can also be modified to express tumor specific antigens, cytokines, and other immune-modulatory molecules. The other strategy to use Ads in cancer therapy is to use oncolytic adenoviruses, which directly kills tumor cells. Gendicine and Advexin are replication-defective recombinant human p53 adenoviral vectors that have been shown to be effective against several types of cancer. Gendi...
Adenoviral Gene Therapy for Renal Cancer Requires Retargeting to Alternative Cellular Receptors1
2002
Metastatic renal cell carcinoma (RCC) is one of the most treatmentresistant malignancies in humans. Therefore, the identification of new agents with better antitumor activity merits a high priority in the treatment of advanced RCC. In this regard, gene therapy with adenoviral (Ad) vectors is a promising new modality for cancer. However, a primary limiting factor for the use of Ad vectors for cancer gene therapy is their critical dependence on cellular expression of the primary Ad receptor, the coxsackie and adenovirus receptor (CAR), known to be down-regulated in many cancer types. Following the identification of CAR deficiency in RCC lines, we have found abundant membrane expression of ␣ v 3 and ␣ v 5 integrins and of the putative receptor to Ad serotype 3 (Ad3). As an alternative gene therapy approach for RCC that would circumvent CAR deficiency, we employed retargeting of replication-incompetent Ad vectors and replication-competent Ad viruses to ␣ v 3 and ␣ v 5 integrins and to the putative Ad3 receptor. These strategies to genetically alter Ad tropism were based on either the insertion of a cysteine-aspartate-cysteine-arginine-glycine-aspartate-cysteine-phenylalanine-cysteine (RGD) motif into the HI loop of the Ad fiber knob domain or on generation of a chimeric Ad fiber composed of adenovirus serotype 5 shaft/Ad3 knob. Both strategies proved highly efficient to circumvent CAR deficiency and enhance gene delivery into RCC cells. Furthermore, in the context of replication-competent Ad, tropism alteration resulted in distinct capacity of the retargeted viruses to infect, replicate, and lyse RCC models in vitro and in vivo. The retargetingstrategieswereparticularlybeneficialinthecontextofreplicationcompetent Ad. These findings underscore the importance of CARindependent cellular entry mechanisms in RCC and are highly consequential for the development of viral antitumor agents for RCC and other CAR-negative tumors.
Molecular Cancer Research, 2008
Conditionally replicative adenovirus (CRAD) represents a promising approach for cancer therapy. Several CRADs controlled by the human telomerase reverse transcriptase promoter have been developed. However, because of their replicative capacity, the importance of cancer specificity for CRADs needs to be further emphasized. In this study, we have developed a novel dual-regulated CRAD, CNHK500-mE, which has its E1a and E1b gene controlled by the human telomerase reverse transcriptase promoter and the hypoxia response element, respectively. It also carries a mouse endostatin expression cassette controlled by the cytomegalovirus promoter. These properties allow for increased cancer cell targeting specificity and decreased adverse side effects. We showed that CNHK500-mE preferentially replicated in cancer cells. Compared with a replication-defective vector carrying the same endostatin expression cassette, CNHK500-mE-mediated transgene expression level was markedly increased via viral replication within cancer cells. In the nasopharyngeal tumor xenograft model, CNHK500-mE injection resulted in antitumor efficacy at day 7 after therapy. Three weeks later, it led to significant inhibition of xenograft tumor growth due to the combined effects of viral oncolytic therapy and antiangiogenesis gene therapy. Pathologic examination showed that most cancer cells were positive for adenoviral capsid protein and for apoptotic terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling in the CNHK500-mE-treated tumor tissues, and the microvessels in these tumor tissues were diminished in quantity and abnormal in morphology. These results suggest that, as a potential cancer therapeutic agent, the CNHK500-mE is endowed with higher specificity to cancer cells and low cytotoxicity to normal cells.
Human Gene Therapy, 2009
Despite some advances, patients with advanced renal cell carcinoma (RCC) cannot usually be cured. Alteration of the natural tropism of adenoviruses may permit more specific gene transfer to target tissues. The aim of this study was to use novel targeting moieties for adenoviral gene therapy of RCC. Previous work in rats suggested that use of Ad5=19p (Ad5 capsid with Ad19p fiber) with kidney vascular targeting moieties HTTHREP (HTT), HITSLLS (HIT), and APASLYN (APA) placed into the fiber knob might be useful for targeting kidney vasculature. Therefore, we sought to investigate the utility of Ad5=19p variants for gene delivery to human RCC cell lines, clinical samples, and orthotopic murine models of metastatic RCC. Six different human RCC cell lines were infected but only Ad5=19p-HIT showed increased transduction, and only in one cell line. Thus, we analyzed human normal and cancerous kidney specimens fresh from patients, which might better mimic the threedimensional architecture of clinical tumors and found that Ad5=19p-HIT showed transduction levels similar to Ad5. In mice, we found that intraperitoneal and intravenous Ad5=19p-HIT transduced tumors at levels comparable to Ad5, and that intratumoral Ad5=19p-HIT was superior to Ad5. Liver tropism was significantly reduced in comparison with Ad5. Improvements in tumor-to-liver transduction ratios suggested that Ad5=19p-HIT may be promising for systemic gene delivery to kidney tumors.