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. 2010 Aug;18(8):1430-9.
doi: 10.1038/mt.2010.98. Epub 2010 Jun 15.

Potentiating cancer immunotherapy using an oncolytic virus

Byram W Bridle  1 , Kyle B Stephenson, Jeanette E Boudreau, Sandeep Koshy, Natasha Kazdhan, Eleanor Pullenayegum, Jérôme Brunellière, Jonathan L Bramson, Brian D Lichty, Yonghong Wan
Affiliations

Potentiating cancer immunotherapy using an oncolytic virus

Byram W Bridle et al. Mol Ther. 2010 Aug.

Abstract

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.

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Figures

Figure 1
Figure 1
Impact of oncolysis and tumor vaccination in naive hosts. C57BL/6 mice received intracranial injections of B16-F10 cells. (a) One week later mice were treated with intravenous injections of VSV-GFP. Fluorescent microscopy revealed that brains harvested 3 days after VSV treatment had evidence of intratumoral GFP expression (inset: upper left panel). Macroscopic examination of brains harvested at day 4 postinfection revealed a large reduction in tumor burden in VSV-GFP-treated brains (upper panels) confirmed by hematoxylin and eosin–stained sections (lower panels). (b) Survival studies failed to detect prolonged survival following oncolytic VSV-GFP treatment (PBS n = 14, VSV-GFP n = 13, pooled data from three experiments). (c) Alternatively, on day 7 postengraftment mice were treated with a single intramuscular dose of Ad-hDCT or Ad-BHG. Immunological analysis of blood was performed on day 14 postvaccination. The percentage of DCT-specific CD8+ T cells are indicated. (d) A significant extension of survival in Ad-hDCT-vaccinated mice was achieved (median survival: Ad-hDCT = 29 days, n = 16 and Ad-BHG = 15 days, n = 14; P < 0.0001, pooled data from three experiments). (e) On day 7 postengraftment, mice bearing intracranial B16 tumors were treated with a single intravenous dose of VSV-hDCT. Immunological analysis of blood was performed 14 days later. The percentage of DCT- and VSV nucleocapsid-specific CD8+ T cells are indicated. (f) Survival studies failed to detect prolonged survival following oncolytic VSV-hDCT treatment (pooled data from three experiments, n = 12 for each treatment). Ad, adenovirus; DCT, dopachrome tautomerase; hDCT, human DCT; PBS, phosphate-buffered saline; VSV, vesicular stomatitis virus.
Figure 2
Figure 2
Turning the immune response against the oncolytic virus into a beneficial one. (a) Timeline for combination treatment with Ad-hDCT and VSV-hDCT. (b) Blood was collected 6 days after VSV treatment and intracellular staining for IFN-γ in response to the dominant epitopes for DCT and the VSV nucleocapsid was performed. (c) Pooled survival data from three independent experiments. Mice were treated with empty Ad vector (Ad-BHG), Ad-hDCT alone, Ad-hDCT followed by VSV-GFP or Ad-hDCT followed by VSV-hDCT (n = 19, n = 18, n = 21, and n = 15, respectively). Median survival: 15, 30, 32, and 54 days, respectively. Ad, adenovirus; DCT, dopachrome tautomerase; hDCT, human DCT; PBS, phosphate-buffered saline; i.c., intracranial; IFN, interferon; i.v., intravenous; VSV, vesicular stomatitis virus.
Figure 3
Figure 3
Immunological features of oncolytic virus immune boosting. (a) Comparison of the numbers of DCT-specific, IFN-γ+ CD8+ T cells in the blood of tumor-bearing (TB, n = 7) and tumor-free (TF, n = 5) C57BL/6 mice at the peak of the response after VSV treatment. (b) Pooled data demonstrating the correlation between the magnitude of the anti-DCT response in the blood and survival. Data includes mice that were mock vaccinated (Ad-BHG, cross), Ad-hDCT vaccinated (open squares) or treated with the Ad-hDCT+VSV-hDCT combination (closed circles). After accounting for group, a unit increase in CD8 resulted in a 29.1% reduction in hazard of death (95% CI 7.2–29.5%), P = 0.0024, hazard ratio 0.809, 95% CI 0.705–0.928. Those three mice having the highest responses actually survived much longer than 100 days. The horizontal lines indicate the mean response achieved in tumor-free mice ± SEM (dashed lines). (c) Ad-hDCT vaccinated C57BL/6 mice bearing intracranial B16-F10 tumors were subsequently treated with PBS, VSV-GFP, or VSV-hDCT. Seven days later, tumors were collected and IFN-γ+ tumor-infiltrating lymphocytes responsive to DCT180–188 peptide were enumerated. (d) gp100-responsive CD8+ T cells were enumerated by intracellular cytokine staining (ICS) for IFN-γ demonstrating that combination therapy of TB animals induces epitope spreading. Limit of detection (LOD) is indicated. Ad, adenovirus; CI, confidence interval; DCT, dopachrome tautomerase; hDCT, human DCT; PBS, phosphate-buffered saline; IFN, interferon; VSV, vesicular stomatitis virus.
Figure 4
Figure 4
Impact of vaccination on OV replication. Tumor-free (TF) or B16-F10 tumor-bearing (TB) C57BL/6 mice were immunized i.m. with Ad vectors as indicated. Fourteen days after Ad treatment, mice were given VSV-hDCT via i.v. injection and the brains were weighed and homogenized 3 days later. (a) Viral titers were quantified by plaque assay and are expressed as pfu/g of brain tissue. Brain weights are summarized in b. Data were pooled from two experiments with 5 mice/group. hDCT, human dopachrome tautomerase; i.m., intramuscularly; i.v., intravenously; VSV, vesicular stomatitis virus.
Figure 5
Figure 5
Impact of vaccination on oncolysis in a lung metastatic model. (a) BALB/c mice were immunized i.m. with Ad-hDCT 14 days before (long interval) or on the same day (short interval) of CT26 tumor engraftment (2 × 105 cells, i.v. injection). Fourteen days after tumor inoculation, mice were treated with 2 × 108 pfu of VSV-hDCT or VSV-GFP via tail-vein injection. (b,c) The whole lungs and brains were harvested and homogenized 4 days after VSV treatment. Viral titers were quantified by plaque assay and expressed as pfu/g of tissue. Data were pooled from two experiments with 5 mice/group. Ad, adenovirus; hDCT, human dopachrome tautomerase; i.m., intramuscularly; i.v., intravenously; VSV, vesicular stomatitis virus.
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