Synergistic antitumour effects of rapamycin and oncolytic reovirus

Abstract

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination.

Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

“…This was presumably due to the induction of autophagic cell death [87,88]. Increased efficacy through modulation of autophagy in similar settings is also described for other OVs [75,76]. The hyperactivation of AKT during mTORC1 inhibition might have benefits when combined with myxoma virus [81][82][83], but in other settings can have a negative effect on survival.…”

“…Combining rapamycin with the highly IFN-sensitive VSV-mutant strain (VSVΔM51) led to significant increase of the oncolytic effect [ 74 ]. In addition other oncolytic RNA viruses, such as NDV and reovirus, showed improved oncolytic effect in mice when co-treated with rapamycin [ 75 , 76 ]. Oncolytic DNA viruses also benefit from co-treatment with rapamycin.…”

The oncolytic efficacy and safety of avian reovirus and its dynamic distribution in infected mice

“…Further research should be undertaken to improve some aspects of reovirus therapy, such as the safety and delivery methods. As multiple ways of treating cancers have become an exciting prospect, a combination of reovirus with chemotherapeutic drugs has shown significant potential advantages, and it is reported that an agent of treating malignant melanoma, rapamycin which combined with reovirus can improve the anti-tumor efficacy, 23 and a combination of reovirus and the immune checkpoint blockade also seems to be a powerful immunotherapy of treating breast cancer. 24 In our study, the ARV showed the significant viral infectivity and efficacy of its oncolytic activity, along with a clear safety profile.…”

Resveratrol, Rapamycin and Metformin as Modulators of Antiviral Pathways

“…The current emphasis is on combining these viruses with molecules that upregulate viral replication, thus increasing oncolysis. Based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis, the antitumor effects of the combination of rapamycin and reovirus was tested in B16F10 cell, a murine model of malignant melanoma, providing evidence of synergistic antitumor cytotoxicity [159].…”