Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus

Abstract

Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

“…The fiber replacement strategy has previously been used with several other serotypes including 3, 7 and 17. 22,24,26,28 These fiber replacements have enabled virus retargeting to, for example, ovarian cancer, central nervous system and airway epithelium. The Ad5/35 hybrid virus has previously been used to target hematopoetic stem cells, dendritic cells and certain breast cancer cells.…”

“…Using this strategy, hybrid adenoviruses have shown favorable tropism profiles for several cell types, including ovarian and breast cancer cells, hematopoetic stem cells, dendritic cells, HUVECs, smooth muscle cells and neurons. 11,[23][24][25][26][27][28] In an attempt to develop a specific gene delivery system for the tumor endothelium, we have analyzed the ability of the recently developed Ad5/35 hybrid virus to transduce endothelial cells in vitro as well as in a rat hepatocellular carcinoma (HCC) model.…”

Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

“…If complete detargeting from CAR is wanted, other strategies should be applied such as mutagenesis of CAR binding amino acids in the fiber knob 11 in conjunction with introducing of the targeting peptide in the HI loop 25 C-terminal of the fiber 35 or hexon. 36 Alternatively the fiber knob 14 or fiber 37 of Ad5 could be exchanged with an alternative serotype. The double binding of Ad5 FWKT (GFP) to SSTR 2 and CAR indicates that the adenoviral knob protein possesses a range of structural plasticity.…”

“…12,13 The adenovirus tropism can be modified through genetic modification of the capsid to target receptors that are highly expressed on tumor cells and thereby avoid CAR deficiency. 14,15 In this study, we investigate Ad5 vectors with fibers modifications for their ability to transduce NET cells. We evaluate an Ad5 with fiber from human adenovirus serotype 35 (Ad5f35), which binds to the CD46 receptor 16 and an Ad5 with fiber knob from human adenovirus serotype 3 (Ad5fk3), which binds to desmoglein 2 (DSG2).…”

Transductional targeting of adenovirus vectors for gene therapy

“…67 Subgroup D Ad receptors include CD46 and a(2-3)-linked sialic acid, a common element of glycolipids. [71][72][73] This fiber pseudotyping approach has identified chimeric vectors with superior infectivity to Ad5 in several clinically relevant cell types, including primary ovarian carcinoma cells, [74][75][76] 81 human cardiovascular tissue 82 and others. 83,84 Interestingly, this strategy has been extended to exploit fiber elements from non-human Ads 85,86 and the fiber-like s1 reovirus attachment protein, which targets cells expressing junctional adhesion molecule.…”