Potentiating Cancer Immunotherapy Using an Oncolytic Virus

Oncolytic viruses (OVs) are highly immunogenic and this limits their use in immune-competent hosts. Although immunosuppression may improve viral oncolysis, this gain is likely achieved at the cost of antitumoral immunity. We have developed a strategy wherein the immune response against the OV leads to enhanced therapeutic outcomes. We demonstrate that immunization with an adenoviral (Ad) vaccine before treatment with an oncolytic vesicular stomatitis virus (VSV) expressing the same tumor antigen (Ag) leads to significantly enhanced antitumoral immunity. Intratumoral replication of VSV was minimally attenuated in Ad-immunized hosts but extending the interval between treatments reduced the attenuating effect and further increased antitumoral immunity. More importantly, our combination approach shifted the immune response from viral Ags to tumor Ags and further reduced OV replication in normal tissues, leading to enhancements in both efficacy and safety. These studies also highlight the benefits of using a replicating, OV to boost a pre-existing antitumoral immune response as this approach generated larger responses versus tumor Ag in tumor-bearing hosts than could be achieved in tumor-free hosts. This strategy should be applicable to other vector combinations, tumor Ags, and tumor targets. Oncolytic viruses (OVs) are highly immunogenic and this limits their use in immune-competent hosts. Although immunosuppression may improve viral oncolysis, this gain is likely achieved at the cost of antitumoral immunity. We have developed a strategy wherein the immune response against the OV leads to enhanced therapeutic outcomes. We demonstrate that immunization with an adenoviral (Ad) vaccine before treatment with an oncolytic vesicular stomatitis virus (VSV) expressing the same tumor antigen (Ag) leads to significantly enhanced antitumoral immunity. Intratumoral replication of VSV was minimally attenuated in Ad-immunized hosts but extending the interval between treatments reduced the attenuating effect and further increased antitumoral immunity. More importantly, our combination approach shifted the immune response from viral Ags to tumor Ags and further reduced OV replication in normal tissues, leading to enhancements in both efficacy and safety. These studies also highlight the benefits of using a replicating, OV to boost a pre-existing antitumoral immune response as this approach generated larger responses versus tumor Ag in tumor-bearing hosts than could be achieved in tumor-free hosts. This strategy should be applicable to other vector combinations, tumor Ags, and tumor targets. IntroductionOncolytic viruses (OVs) cure cancer in animal models if they infect tumors and replicate extensively to mediate complete destruction.1Bischoff JR Kirn DH Williams A Heise C Horn S Muna M et al.An adenovirus mutant that replicates selectively in p53-deficient human tumor cells.Science. 1996; 274: 373-376Crossref PubMed Scopus (1558) Google Scholar,2Grote D Russell SJ Cornu TI Cattaneo R Vile R Poland GA et al.Live attenuated measles virus induces regression of human lymphoma xenografts in immunodeficient mice.Blood. 2001; 97: 3746-3754Crossref PubMed Scopus (212) Google Scholar,3Hummel JL Safroneeva E Mossman KL The role of ICP0-Null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma.Mol Ther. 2005; 12: 1101-1110Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,4Stojdl DF Lichty B Knowles S Marius R Atkins H Sonenberg N et al.Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.Nat Med. 2000; 6: 821-825Crossref PubMed Scopus (656) Google Scholar,5Stojdl DF Lichty BD tenOever BR Paterson JM Power AT Knowles S et al.VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents.Cancer Cell. 2003; 4: 263-275Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar,6Wilcox ME Yang W Senger D Rewcastle NB Morris DG Brasher PM et al.Reovirus as an oncolytic agent against experimental human malignant gliomas.J Natl Cancer Inst. 2001; 93: 903-912Crossref PubMed Scopus (192) Google Scholar However, broad clinical application requires treating immunocompetent hosts bearing malignancies that may have partially intact antiviral mechanisms. An active host immune response against the virus that rapidly eliminates viral replication, leading to incomplete or transient tumor destruction represents an important barrier to success.7Cattaneo R Miest T Shashkova EV Barry MA Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded.Nat Rev Microbiol. 2008; 6: 529-540Crossref PubMed Scopus (294) Google Scholar It has been shown in naive animals that the development of an acquired immune response usually takes less than a week, leaving a small window of opportunity for oncolytic vectors to function.8Paiva LR Binny C Ferreira Jr, SC Martins ML A multiscale mathematical model for oncolytic virotherapy.Cancer Res. 2009; 69: 1205-1211Crossref PubMed Scopus (57) Google Scholar,9Russell SJ Peng KW Viruses as anticancer Full Text Full Text PDF PubMed Scopus Google Scholar viral replication or the same a of have been from M A et of oncolytic vesicular stomatitis virus of responses in Ther. 2008; Full Text Full Text PDF PubMed Scopus Google M A et oncolytic of vesicular stomatitis virus of and Ther. 2009; PubMed Scopus Google ML D B et an oncolytic adenovirus in Ther. Full Text Full Text PDF PubMed Scopus Google H of a oncolytic virus and a effect and tumor-specific immune Res. PubMed Scopus Google Scholar to the use of R R et as to to Ther. 2005; 12: PubMed Scopus Google B C et a strategy for systemic of oncolytic measles viruses in cancer Ther. Full Text Full Text PDF PubMed Scopus Google S MA as for of oncolytic Cancer Ther. PubMed Scopus Google AT Paterson JM Lichty BD et of an oncolytic virus antiviral Ther. Full Text Full Text PDF PubMed Scopus Google Scholar or viral MA N JM and immune responses against the virus and for in the 2001; PubMed Scopus Google S M et adenovirus vectors the of and Med. 2005; PubMed Scopus Google adenovirus and Ther. 2001; PubMed Scopus Google H A of adenovirus immune Ther. 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Full Text Full Text PDF PubMed Scopus Google H of a oncolytic virus and a effect and tumor-specific immune Res. PubMed Scopus Google R R et as to to Ther. 2005; 12: PubMed Scopus Google B C et a strategy for systemic of oncolytic measles viruses in cancer Ther. Full Text Full Text PDF PubMed Scopus Google S MA as for of oncolytic Cancer Ther. PubMed Scopus Google AT Paterson JM Lichty BD et of an oncolytic virus antiviral Ther. Full Text Full Text PDF PubMed Scopus Google S M et adenovirus vectors the of and Med. 2005; PubMed Scopus Google H A of adenovirus immune Ther. PubMed Scopus Google Scholar However, is that oncolytic viral antitumoral immunity in JL Safroneeva E Mossman KL The role of ICP0-Null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma.Mol Ther. 2005; 12: 1101-1110Abstract Full Text Full Text PDF PubMed Scopus (45) Google T M M T M et cancer with a for the treatment of of Ther. 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An active host immune response against the virus that rapidly eliminates viral replication, leading to incomplete or transient tumor destruction represents an important barrier to success.7Cattaneo R Miest T Shashkova EV Barry MA Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded.Nat Rev Microbiol. 2008; 6: 529-540Crossref PubMed Scopus (294) Google Scholar It has been shown in naive animals that the development of an acquired immune response usually takes less than a week, leaving a small window of opportunity for oncolytic vectors to function.8Paiva LR Binny C Ferreira Jr, SC Martins ML A multiscale mathematical model for oncolytic virotherapy.Cancer Res. 2009; 69: 1205-1211Crossref PubMed Scopus (57) Google Scholar,9Russell SJ Peng KW Viruses as anticancer Full Text Full Text PDF PubMed Scopus Google Scholar viral replication or the same a of have been from M A et of oncolytic vesicular stomatitis virus of responses in Ther. 2008; Full Text Full Text PDF PubMed Scopus Google M A et oncolytic of vesicular stomatitis virus of and Ther. 2009; PubMed Scopus Google ML D B et an oncolytic adenovirus in Ther. Full Text Full Text PDF PubMed Scopus Google H of a oncolytic virus and a effect and tumor-specific immune Res. PubMed Scopus Google Scholar to the use of R R et as to to Ther. 2005; 12: PubMed Scopus Google B C et a strategy for systemic of oncolytic measles viruses in cancer Ther. Full Text Full Text PDF PubMed Scopus Google S MA as for of oncolytic Cancer Ther. PubMed Scopus Google AT Paterson JM Lichty BD et of an oncolytic virus antiviral Ther. Full Text Full Text PDF PubMed Scopus Google Scholar or viral MA N JM and immune responses against the virus and for in the 2001; PubMed Scopus Google S M et adenovirus vectors the of and Med. 2005; PubMed Scopus Google adenovirus and Ther. 2001; PubMed Scopus Google H A of adenovirus immune Ther. PubMed Scopus Google that the immune response that viral be transient in could the immune response to be a that the therapeutic of the We that the OV to a antigen (Ag) and using this virus in a host that has been previously against this same could this a the response against the the response against viral Ags leading to a antitumoral immune the tumor Ag in the OV is a response against this Ag viral to tumors in The response against this Ag viral replication the this tumor-specific T than T are the tumor in the of tumor that in viral in a host be than for the response that the oncolytic vaccine vector as this a antitumoral response the tumor to malignant This may to both a transient oncolytic effect and an enhanced antitumoral immune response that is in our a adenovirus (Ad) as a vaccine vector and a vesicular stomatitis virus (VSV) as an oncolytic vaccine virus in that tumors in the or DF Lichty B Knowles S Marius R Atkins H Sonenberg N et al.Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.Nat Med. 2000; 6: 821-825Crossref PubMed Scopus (656) Google C JL is a of to the Res. PubMed Scopus Google Scholar We have previously vectors as vaccine vectors and that they to and boost an immune Lichty BD S et stomatitis virus as a cancer vaccine vector to immunity to with Ther. 2009; Full Text Full Text PDF PubMed Scopus Google Lichty BD of adenoviral immunization with a vesicular stomatitis Ther. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar We demonstrate that treatment of a tumor-bearing host with and oncolytic VSV both expressing a a antitumoral immune with VSV the tumor viral This approach leads to increased tumor and benefits that with the use of viral or tumor These studies demonstrate the of as of antitumoral immunity as larger responses are achieved in tumor-bearing hosts to of the vector in the tumor that against a tumor Ag an oncolytic vaccine virus the immune response that the response against the tumor the immune response against viral Ags for transient viral leading to and antitumoral immunity and enhanced safety.

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