Combination therapy with radiation or cisplatin enhances the potency of Ad5/35 chimeric oncolytic adenovirus in a preclinical model of head and neck cancer

Abstract

Ad5/35 chimeric oncolytic viruses (OVs) have earlier been shown to increase the level of vector transduction, intratumoral virus spread and survival in a number of xenograft models when compared with Ad5-based viruses. Because radiation and chemotherapy are the current standards of care for most cancer indications, Ad5/35 OVs have been tested here in combination with either radiation or chemotherapy in a head and neck cancer (HNC) xenograft model to determine whether such combination therapies enhance the potency of the virus, thereby leading to a greater therapeutic effect. In mice treated with either Ad5 OV (OV-5) or Ad5/ 35 chimeric OV (OV-5T35H), there was a delay in tumor progression compared with animals treated with phosphate-buffered saline (PBS) alone. When Ad5/35 chimeric OV and radiation were used in combination, there was a further delay in tumor progression, which resulted in a significant increase in the mean survival time of tumor-bearing mice compared with Ad5/35 or Ad5 OV monotherapy or to the combination of Ad5 OV with radiation, which was significantly less potent (Po0.0001) compared with the Ad5/35 OV plus radiation combination. Similarly, a combination of Ad5/35 chimeric OV with cisplatin significantly delayed tumor progression compared with Ad5/35 OV or Ad5 OV virus alone or with the combination of Ad5 virus with cisplatin (Po0.01). In summary, the combination of the potent Ad5/35 chimeric OV with either radiation or chemotherapy leads to significantly increased survival of mice bearing highly aggressive tumors, and may therefore offer an effective treatment strategy for patients with difficult to treat HNC.

Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression

“…These findings are in line with the literature. Both cisplatin and radiation have been shown to reduce body weight [54-57]. Further, chemotherapy treatment can suppress voluntary activity, including decreased running wheel [17, 58-61] and open field activity [56, 57].…”

Strategies to Enhance Viral Penetration of Solid Tumors

“…This presents another physical barrier obstructing the movement of the relatively large viral particles between cells. As mentioned previously, several studies have shown that a combination of apoptosisinducing drugs and oncolytic therapy results in increased viral spread within tumors and a synergistic antitumor effect (Raki et al, 2005;reviewed in Mi et al, 2001;Yun, 2008;Ganesh et al, 2009). This may be due, at least in part, to the increased viral release and the formation of apoptotic bodies, but may also be attributed to the increase in interstitial space created by the apoptotic cells.…”

“…The synergistic effects of apoptosis-inducing drugs and viral therapy have been well documented (Raki et al, 2005;reviewed in Mi et al, 2001;Yun, 2008;Ganesh et al, 2009). In addition, adenoviruses with mutated E1B-19kD, a gene that inhibits apoptosis, have increased antitumor efficacy compared with E1B-19kD competent viruses (Sauthoff et al, 2000;Kim et al, 2002;Yoon et al, 2006).…”

Recent advances in oncolytic virus design

“…The most studied regimens consist of OVs in combination with chemotherapeutic agents, including 5-fluorouracil [87], cisplatin [88], oxaliplatin [37], gemcitabine [89], temozolomide [90] and taxanes (e.g., docetaxel and paclitaxel) [91,92]. Cooperation with radiotherapy has also been described [88].…”