Abstract
Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1) physical retargeting, (2) physical detargeting, (3) chemical shielding, or (4) by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells. We explored the utility of these approaches with oncolytic adenovirus serotype 5 (Ad5) in immunocompetent Syrian hamsters bearing subcutaneous HaK tumors. After a single intravenous injection to reach the distant tumors, the physically hepatocyte-detargeted virus Ad5-hexon-BAP was more effective than conditionally replicating Ad5-dl1101/07 with mutations in its E1A protein. When these control or Ad5 treated animals were treated a second time by intratumoral injection, prior exposure to Ad5 did not affect tumor growth, suggesting that anti-Ad immunity neither prevented treatment nor amplified anti-tumor immune responses. Ad5-dl1101/07 was next chemically shielded with polyethylene glycol (PEG). While 5 kDa of PEG blunted pro-inflammatory IL-6 production induced by Ad5-dl1101/07, this shielding reduced Ad oncolytic activity.
Highlights
Adenoviruses (Ads) are non-enveloped double-stranded DNA viruses that are being tested for oncolytic virotherapy
We explored the role of Kupffer cells and hepatocytes as barriers to systemic therapy for adenovirus serotype 5 (Ad5) using pharmacological interventions [5]
PEGylated Ad5 reduces in vitro coxsackie and adenovirus receptor (CAR)-dependent infection by four to five orders of magnitude in vitro, but did not reduce in vivo oncolytic activity of the virus to control tumors derived from LNCaP human prostate cancer cells in nude mice after intravenous injection [17]
Summary
Adenoviruses (Ads) are non-enveloped double-stranded DNA viruses that are being tested for oncolytic virotherapy (reviewed in [1,2]). PEGylated Ad5 reduces in vitro coxsackie and adenovirus receptor (CAR)-dependent infection by four to five orders of magnitude in vitro, but did not reduce in vivo oncolytic activity of the virus to control tumors derived from LNCaP human prostate cancer cells in nude mice after intravenous injection [17]. This suggested that CAR interactions were less important in vivo for targeting distant tumors after intravenous injection. CRAd strategy with PEG chemical physical detargeting and find that this chemical strategy results in reductions in efficacy following single treatment in hamsters
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