Abstract
Reovirus is under development as a therapeutic for numerous types of cancer. In contrast to other oncolytic viruses, the safety and efficacy of reovirus have not been improved through genetic manipulation. Here, we tested the oncolytic capacity of recombinant strains (rs) of prototype reovirus laboratory strains T1L and T3D (rsT1L and rsT3D, respectively) in a panel of non-small cell lung cancer (NSCLC) cell lines. We found that rsT1L was markedly more cytolytic than rsT3D in the large cell carcinoma cell lines tested, whereas killing of adenocarcinoma cell lines was comparable between rsT1L and rsT3D. Importantly, non-recombinant T1L and T3D phenocopied the kinetics and magnitude of cell death induced by recombinant strains. We identified gene segments L2, L3, and M1 as viral determinants of strain-specific differences cell killing of the large cell carcinoma cell lines. Together, these results indicate that recombinant reoviruses recapitulate the cell killing properties of non-recombinant, tissue culture-passaged strains. These studies provide a baseline for the use of reverse genetics with the specific objective of engineering more effective reovirus oncolytics. This work raises the possibility that type 1 reoviruses may have the capacity to serve as more effective oncolytics than type 3 reoviruses in some tumor types.
Highlights
Oncolytic viruses are an emerging class of cancer therapeutics that selectively replicate in and kill transformed cells while sparing non-transformed cells [1,2]
Recombinant Reovirus Strains rsT1L and rsT3D Differ in the Capacity to Kill Large Cell Carcinoma
To assess the oncolytic capacity of recombinant reoviruses, we infected a panel of non-small cell lung cancer (NSCLC) cell lines (Table 1) with recombinant or non-recombinant (T1L or type 3 Dearing (T3D)) reoviruses
Summary
Oncolytic viruses are an emerging class of cancer therapeutics that selectively replicate in and kill transformed cells while sparing non-transformed cells [1,2]. Mammalian orthoreovirus (reovirus) is one of a number of viruses with oncolytic potential that are in different stages of development [2,3,4,5,6]. Reovirus shows efficacy as a virotherapeutic agent for aggressive and refractory human tumors [8]. Phases I and II clinical trials in the United States, Canada, and Europe demonstrate that pelareorep (Reolysin), a first-generation reovirus therapeutic is tolerated and safe, even in patients with advanced cancer who have undergone extensive chemotherapy [9,10]. A Phase III clinical trial to test reovirus efficacy against head and neck cancers was recently completed
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