Intratumoral INF-γ triggers an antiviral state in GL261 tumor cells: a major hurdle to overcome for oncolytic vaccinia virus therapy of cancer.
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ABSTRACT:
SUBMITTER: Kober C
PROVIDER: S-EPMC4782962 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Background: Newly emerging cancer immunotherapy has led to significant progress in cancer treatment; however, its efficacy is limited in solid tumors since the majority of them are "cold" tumors. Oncolytic viruses, especially when properly armed, can directly target tumor cells and indirectly modulate the tumor microenvironment (TME), resulting in "hot" tumors. These viruses can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies. Cytokines are good candidates to arm oncolytic viruses. IL-23, an IL-12 cytokine family member, plays many roles in cancer immunity. Here, we used oncolytic vaccinia viruses to deliver IL-23 variants into the tumor bed and explored their activity in cancer treatment on multiple tumor models. Methods: Oncolytic vaccinia viruses expressing IL-23 variants were generated by homologue recombination. The characteristics of these viruses were in vitro evaluated by RT-qPCR, ELISA, flow cytometry and cytotoxicity assay. The antitumor effects of these viruses were evaluated on multiple tumor models in vivo and the mechanisms were investigated by RT-qPCR and flow cytometry. Results: IL-23 prolonged viral persistence, probably mediated by up-regulated IL-10. The sustainable IL-23 expression and viral oncolysis elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, TNF-α, Perforin, IL-2, Granzyme B and activated T cells in the TME, transforming the TME to be more conducive to antitumor immunity. This leads to a systemic antitumor effect which is dependent on CD8+ and CD4+ T cells and IFN-γ. Oncolytic vaccinia viruses could not deliver stable IL-23A to the tumor, attributed to the elevated tristetraprolin which can destabilize the IL-23A mRNA after the viral treatment; whereas vaccinia viruses could deliver membrane-bound IL-23 to elicit a potent antitumor effect which might avoid the possible toxicity normally associated with systemic cytokine exposure. Conclusion: Either secreted or membrane-bound IL-23-armed vaccinia virus can induce potent antitumor effects and IL-23 is a candidate cytokine to arm oncolytic viruses for cancer immunotherapy.
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Project description:Oncolytic vaccina virus (oncoVV) used for cancer therapy has progressed in recent years. Here, a gene encoding white-spotted charr lectin (WCL) was inserted into an oncoVV vector to form an oncoVV-WCL recombinant virus. OncoVV-WCL induced higher levels of apoptosis and cytotoxicity, and replicated faster than control virus in cancer cells. OncoVV-WCL promoted IRF-3 transcriptional activity to induce higher levels of type I interferons (IFNs) and blocked the IFN-induced antiviral response by inhibiting the activity of IFN-stimulated responsive element (ISRE) and the expression of interferon-stimulated genes (ISGs). The higher levels of viral replication and antitumor activity of oncoVV-WCL were further demonstrated in a mouse xenograft tumor model. Therefore, the engineered oncoVV expressing WCL might provide a new avenue for anticancer gene therapy.
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Project description:Pexa-Vec (pexastimogene devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia virus designed to destroy cancer cells through viral lysis and induction of granulocyte-macrophage colony-stimulating factor (GM-CSF)-driven tumor-specific immunity. Pexa-Vec has undergone phase 1 and 2 testing alone and in combination with other therapies in adult patients, via both intratumoral and intravenous administration routes. We sought to determine the safety of intratumoral administration in pediatric patients. In a dose-escalation study using either 10(6) or 10(7) plaque-forming units per kilogram, we performed one-time injections in up to three tumor sites in five pediatric patients and two injections in one patient. Ages at study entry ranged from 4 to 21 years, and their cancer diagnoses included neuroblastoma, hepatocellular carcinoma, and Ewing sarcoma. All toxicities were ≤ grade 3. The most common side effects were sinus fever and sinus tachycardia. All three patients at the higher dose developed asymptomatic grade 1 treatment-related skin pustules that resolved within 3-4 weeks. One patient showed imaging evidence suggestive of antitumor biological activity. The two patients tested for cellular immunoreactivity to vaccinia antigens showed strong responses. Overall, our study suggests Pexa-Vec is safe to administer to pediatric patients by intratumoral administration and could be studied further in this patient population.
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Project description:BackgroundOncolytic viruses (OVs) are an attractive way to increase immune infiltration into an otherwise cold tumor. While OVs are engineered to selectively infect tumor cells, there is evidence that they can infect other non-malignant cells in the tumor. We sought to determine if oncolytic vaccinia virus (VV) can infect lymphocytes in the tumor and, if so, how this was linked to therapeutic efficacy.MethodsTo investigate infection of lymphocytes by VV, we used a GFP reporting VV in a murine head and neck squamous cell carcinoma tumor model. We also performed in vitro infection studies to determine the mechanism and consequences of VV lymphocyte infection by VV.ResultsOur findings show that VV carries the capacity to infect proportions of immune cells, most notably T cells, after intratumoral treatment. Notably, this infection is preferential to terminally differentiated T cells that tend to reside in hypoxia. Infection of T cells leads to both virus production by the T cells as well as the eventual death of these cells. Using a mouse model which overexpressed the antiapoptotic protein Bcl2 in all T cells, we found that reducing T cell death following VV infection in MEER tumors reduced the number of complete regressions and reduced survival time compared with littermate control mice.ConclusionsThese findings suggest that OVs are capable of infecting more than just malignant cells after treatment, and that this infection may be an important part of the OV mechanism. We found that exhausted CD8+ T cells and regulatory CD4+ T cells were preferentially infected at early timepoints after treatment and subsequently died. When cell death in T cells was mitigated, mice responded poorly to VV treatment, suggesting that the deletion of these populations is critical to the therapeutic response to VV.
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Project description:Ionizing radiation (IR) and oncolytic viruses are both used to treat cancer, and the effectiveness of both agents depends upon stimulating an immune response against the tumor. In this study we tested whether combining image guided ionizing radiation (IG-IR) with an oncolytic vaccinia virus (VACV) could yield a better therapeutic response than either treatment alone. ΔF4LΔJ2R VACV grew well on irradiated human and mouse breast cancer cells, and the virus can be combined with 4 or 8 Gy of IR to kill cells in an additive or weakly synergistic manner. To test efficacy in vivo we used immune competent mice bearing orthotopic TUBO mammary tumors. IG-IR worked well with 10 Gy producing 80% complete responses, but this was halved when the tumors were treated with VACV starting 2 days after IG-IR. VACV monotherapy was ineffective in this model. The antagonism was time dependent as waiting for 21 days after IG-IR eliminated the inhibitory effect but without yielding any further benefits over IR alone. In irradiated tumors, VACV replication was also lower, suggesting that irradiation created an environment that did not support infection as well in vivo as in vitro. A study of how four different treatment regimens affected the immune composition of the tumor microenvironment showed that treating irradiated tumors with VACV altered the immunological profiles in tumors exposed to IR or VACV alone. We detected more PD-1 and PD-L1 expression in tumors exposed to IR+VACV but adding an αPD-1 antibody to the protocol did not change the way VACV interferes with IG-IR therapy. VACV encodes many immunosuppressive gene products that may interfere with the ability of radiotherapy to induce an effective anti-tumor immune response through the release of danger-associated molecular patterns. These data suggest that infecting irradiated tumors with VACV, too soon after exposure, may interfere in the innate and linked adaptive immune responses that are triggered by radiotherapy to achieve a beneficial impact.
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Project description:Cancer is still a leading of cause of death worldwide. Among the bio-therapy strategies for cancer, vaccinia virus (VV) has been widely used as an expression vector because of its potent oncolytic activities in addition to its large capacity for insertion of foreign genes and excellent safety records. In the present study, a novel recombinant VV, VV-HBD2-lacZ, expressing human β-defensin 2 (HBD2), an anti-microbial peptide of the innate immune system, was constructed. First, the chemotaxis characteristics of HBD2 expressed on VV-HBD2-lacZ-infected cells toward dendritic cells (DCs) in vitro and in vivo were demonstrated. The anti-tumor effects of VV-HBD2-lacZ in vitro and in vivo in a mouse melanoma cancer model were then investigated. It was found that VV-HBD2-lacZ was able to inhibit tumor growth and metastasis significantly. It was further demonstrated that VV-HBD2-lacZ induced potent cytotoxic activity by increasing the tumor-infiltrating CD4+ and CD8+ T cells. These results indicate that HBD2-expressing VV recruited plasmacytoid DCs (pDCs) to the tumor location, leading to cytotoxic T cell response against the tumor, and thus inhibited tumor growth in vitro and in vivo. In conclusion, oncolytic HBD2-expressing VV provides an effective treatment for tumors by triggering innate and adaptive immunity.
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Project description:Oncolytic virotherapy (OVT) is a promising form of cancer treatment that uses genetically engineered viruses to replicate within cancer cells and trigger anti-tumor immune response. In addition to killing cancer cells, oncolytic viruses can also remodel the tumor microenvironment and stimulate a long-term anti-tumor immune response. Despite achieving positive results in cellular and organismal studies, there are currently only a few approved oncolytic viruses for clinical use. Vaccinia virus (VACV) has emerged as a potential candidate due to its ability to infect a wide range of cancer cells. This review discusses the mechanisms, benefits, and clinical trials of oncolytic VACVs. The safety and efficacy of different viral backbones are explored, as well as the effects of oncolytic VACVs on the tumor microenvironment. The potential combination of oncolytic VACVs with immunotherapy or traditional therapies is also highlighted. The review concludes by addressing prospects and challenges in the field of oncolytic VACVs, with the aim of promoting further research and application in cancer therapy.
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Project description:Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib.Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. Cancer Res; 78(4); 922-37. ©2017 AACR.
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