Enhanced antitumor efficacy of fiber‐modified, midkine promoter‐regulated oncolytic adenovirus in human malignant mesothelioma

Abstract

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus ⁄ adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma.

Whole cell vaccination using immunogenic cell death by an oncolytic adenovirus is effective against a colorectal cancer model

“…We tested two adenoviral vectors illustrated in Figure 1a. 25,26 The replication-defective vector Ad884 did not induce apparent cell death at a multiplicity of infection (MOI) of up to 100 in human DLD-1 cells or up to 1,000 in murine CRC cell lines (CMT93 and CT26) and fibroblasts (Figure 1b). In contrast, a conditionally replicating oncolytic vector, Ad881, in which the adenoviral E1 gene is driven by the midkine promoter, showed dose-dependent cytotoxicity in DLD-1, CT26, and CMT93 cells, but not in fibroblasts (Figure 1c).…”

“…25,26 Ad881 is a conditionally replicating oncolytic adenovirus in which the adenoviral E1 gene is driven by the midkine promoter. Ad884 is a replication-defective adenovirus that was used as a control nononcolytic adenovirus.…”

Selective effects of a fiber chimeric conditionally replicative adenovirus armed with hep27 gene on renal cancer cell

“…These data clearly showed 5/35 fiber-modified adenoviral vector had efficient infection for renal cancer cells in our experiment, which was consistent with reports from different investigators. 10,23,24 Hep27 is a short-chain dehydrogenase/reductase, which is synthesized in human hepatoblastoma HepG2 cells following growth arrest induced by butyrate treatment. 15 Hep27 could translocate to the nucleus and bind to Mdm2, resulting in the attenuation of Mdm2-mediated p53 degradation.…”

“…Ad35 attaches to cells via a non-CAR receptor, CD46 instead, a membrane cofactor protein. 10 CD46 was wildly expressed on most cancer cells. Herein, the adenoviral vector with a chimeric fiber consisting of the knob and shaft of Ad35 relative to Ad5 was constructed.…”

Expression of p53 synergistically augments caspases-mediated apoptosis induced by replication-competent adenoviruses in pancreatic carcinoma cells

“…Ad5 bearing type 35-derived fiber-knob region (AdF) can augment the infectivity in particular to tumor cells expressing CAR at a low level. 8,9 The chimeric AdF have another advantage in terms of gene transfer. AdF in combination with Ad5 vectors can transduce target cells with two different genes encoded by the respective vectors.…”