Steve H Thorne

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (38)298.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Oncolytic vaccinia virus has been shown to induce a profound, rapid and tumor-specific vascular collapse in both preclinical models and in clinical studies, however a complete examination of the kinetics and levels of collapse and revascularization has not been described previously. Contrast-enhanced ultrasound was used to follow tumor perfusion levels in mouse tumor models at times after vaccinia therapy. It was observed that re-vascularization after viral therapy was dramatically delayed and did not occur until after viral clearance. This indicated that oncolytic vaccinia may posses a previously undescribed anti-angiogenic potential that might synergize with the reported anti-vascular effects. Despite a rapid loss of perfusion and widespread hypoxia within the tumor it was observed that VEGF levels in the tumor were suppressed throughout the period of active viral infection. Although tumor vasculature could eventually reform after the viral therapy was cleared in mouse models, anti-tumor effects could be significantly enhanced through additional combination with anti-VEGF therapies. This was initially examined using a gene therapy approach (Ad-Flk1-Fc) to target VEGF directly, demonstrating that the timing of application of the anti-angiogenic therapy was critical. However, it is also known that oncolytic vaccinia sensitizes tumors to tyrosine kinase inhibitors (TKI) in the clinic through an unknown mechanism. It is possible this phenomenon may be mediated through the anti-angiogenic effects of the TKIs. This was modeled in mouse tumors using sunitinib in combination with oncolytic vaccinia. It was observed that prevention of angiogenesis mediated by oncolytic vaccinia can be utilized to enhance the TKI therapy. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 01/2014; · 6.20 Impact Factor
  • Steven M Albelda, Steve H Thorne
    Molecular Therapy 01/2014; 22(1):6-8. · 7.04 Impact Factor
  • Steve H Thorne
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    ABSTRACT: Evaluation of: Kanerva A, Nokisalmi P, Diaconu I et al. Antiviral and anti-tumor T-cell immunity in patients treated with GM-CSF coding oncolytic adenovirus. Clin. Cancer Res. 19(10), 2734-2744 (2013). The field of oncolytic viral therapy has been reinvigorated recently with publication of clinical data from two leading vectors, one based on HSV and one on Vaccinia, both of which express GM-CSF. Part of the reason for the improved clinical results with these vectors appears to be the enhanced immunotherapeutic mechanism of tumor destruction mediated by GM-CSF expression itself. The article by Kanerva et al. extends this work to describe early clinical use of an oncolytic adenovirus expressing GM-CSF, although the data are too preliminary to describe significant therapeutic benefits of GM-CSF expression in this backbone. However, the description of enhanced antitumor immunity in those patients that developed greater antiviral immunity after treatment provides a potent demonstration of the immunotherapeutic potential of epitope spreading after treatment with oncolytic viral therapies.
    Immunotherapy 08/2013; 5(8):817-9. · 2.39 Impact Factor
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    ABSTRACT: Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, β-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-naïve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically. Cancer Res; 73(4); 1-75. ©2012 AACR.
    Cancer Research 02/2013; · 9.28 Impact Factor
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    ABSTRACT: The combination of an oncolytic virus, that directly destroys tumor cells and mediates an acute immune response, with an immune cell therapy, capable of further enlisting and enhancing the host immune response, has the potential to create a potent therapeutic effect. We have previously developed several strategies for optimizing the delivery of oncolytic vaccinia virus vectors to their tumor targets, including the use of immune cell-based carrier vehicles and the incorporation of mutations that increase production of the enveloped form of vaccinia (extracellular enveloped viral (EEV)) that is better adapted to spread within a host. Here, we initially combine these approaches to create a novel therapeutic, consisting of an immune cell (cytokine-induced killer, CIK) preloaded with an oncolytic virus that is EEV enhanced. This resulted in direct interaction between the viral and immune cell components with each assisting the other in directing the therapy to the tumor and so enhancing the antitumor effects. This effect could be further improved through CCL5 expression from the virus. The resulting multicomponent therapy displays the ability for synergistic crosstalk between components, so significantly enhancing tumor trafficking and antitumor effects.Molecular Therapy (2012); doi:10.1038/mt.2012.257.
    Molecular Therapy 12/2012; · 7.04 Impact Factor
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    ABSTRACT: Promising phase II clinical results have been reported recently for several oncolytic viral therapeutics, including strains based on vaccinia virus. One reason for this has been an increased appreciation of the critical therapeutic importance of the immune response raised by these viruses. However, the most commonly used approaches to enhance these immunotherapeutic effects in oncolytic viruses, typically though expression of cytokine transgenes, often also result in a reduction in oncolytic activity and premature clearance of the virotherapy from the tumor. Approaches that enhance the immunotherapeutic effects while maintaining oncolytic activity would therefore be beneficial. Here, it is demonstrated that the expression of the chemokine CCL19 (ELC) from an oncolytic vaccinia virus (vvCCL19) results in increased antitumor effects in syngeneic mouse tumor models. This corresponded with increased t cell and dendritic cell infiltration into the tumor. However, vvCCL19 persisted in the tumor at equivalent levels to a control virus without CCL19, demonstrating that oncolytic activity was not curtailed. Instead, vvCCL19 was cleared rapidly and selectively from normal tissues and organs, indicating a potentially increased safety profile. The therapeutic activity of vvCCL19 could be further significantly increased through combination with adoptive transfer of therapeutic immune cells expressing CCR7, the receptor for CCL19. This approach therefore represents a means to increase the safety and therapeutic benefit of oncolytic viruses, used alone or in combination with immune cell therapies.
    Neoplasia (New York, N.Y.) 12/2012; 14(12):1115-21. · 5.48 Impact Factor
  • Steve H Thorne
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    ABSTRACT: Oncolytic vaccinia viruses have made some impressive advances over the last 5 years, with a range of -different backbones displaying significant antitumor responses in preclinical models, and some exciting clinical results being reported against liver cancers. Because the virus is capable of rapid spread within the tumor, has evolved to spread relatively undetected within the blood stream, does not integrate into the host cell chromosome, and can infect almost any cell type, it is well-suited to the requirements for a successful oncolytic. In addition, the extensive clinical use of this virus means that contraindications to its use are known, and approved and experimental antivirals are available. Furthermore, because the virus has a large array of virulence genes whose deletion may target different properties of the cancer cell, and a large cloning capacity allowing for insertion of multiple transgenes, the possibilities for further development of novel and next-generation oncolytic vectors are multitude.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 797:205-15. · 1.29 Impact Factor
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    Juan J Rojas, Steve H Thorne
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    ABSTRACT: Biological cancer therapies, such as oncolytic, or replication-selective viruses have advantages over traditional therapeutics as they can employ multiple different mechanisms to target and destroy cancers (including direct cell lysis, immune activation and vascular collapse). This has led to their rapid recent clinical development. However this also makes their pre-clinical and clinical study complex, as many parameters may affect their therapeutic potential and so defining reason for treatment failure or approaches that might enhance their therapeutic activity can be complicated. The ability to non-invasively image viral gene expression in vivo both in pre-clinical models and during clinical testing will considerably enhance the speed of oncolytic virus development as well as increasing the level and type of useful data produced from these studies. Further, subsequent to future clinical approval, imaging of reporter gene expression might be used to evaluate the likelihood of response to oncolytic viral therapy prior to changes in tumor burden. Here different reporter genes used in conjunction with oncolytic viral therapy are described, along with the imaging modalities used to measure their expression, while their applications both in pre-clinical and clinical testing are discussed. Possible future applications for reporter gene expression from oncolytic viruses in the phenotyping of tumors and the personalizing of treatment regimens are also discussed.
    Theranostics 01/2012; 2(4):363-73. · 7.81 Impact Factor
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    ABSTRACT: Preclinical studies have demonstrated that, unlike oncolytic adenoviruses, oncolytic vaccinia viruses can reach implanted tumors upon systemic injection. However, the biodistribution of this oncolytic agent in in situ autochthonous tumor models remains poorly characterized. In the present study, we assessed this biodistribution in a model of mouse hepatocellular carcinoma (HCC) obtained after injection of the carcinogen diethylnitrosamine (DEN). Twelve months after DEN administration, histology, quantitative reverse transcription-polymerase chain reaction, in situ hybridization and viral titration were used to characterize tumors, as well as to assess the viral load of the livers upon either intravenous or intraperitoineal injection. The results obtained showed that the architecture of the liver was lost, with a noticeable absence of sinusoids, as well as the presence of steatosis and α-fetoprotein-positive HCC tumor nodules. Bioluminescence imaging and measures of the infective virus load demonstrated that intravenous injection of 10(8)  plaque-forming units of the recombinant vaccinia virus led to a predominant transduction of the liver, whereas intraperitoneal injection resulted in a lower level of liver transduction accompanied by an increased infection of the lungs, spleen, kidneys and bowels. Immunohistochemical analysis of liver sections of animals injected intravenously with the virus revealed a preferential localization of vaccinia-specific immunoreactivity in the tumors. The findings of the present study emphasize the importance of the route of administration of the vector and highlight the relevance of systemic injection of oncolytic vaccinia virus in the context of hepatocellular carcinoma.
    The Journal of Gene Medicine 10/2011; 13(12):692-701. · 2.16 Impact Factor
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    ABSTRACT: Oncolytic viruses (OVs) are designed to replicate in, and subsequently lyse cancer cells. Numerous oncolytic virus platforms are currently in development. Here we review preclinical and clinical experience with JX-594, the lead candidate from the targeted and armed oncolytic poxvirus class. JX-594 is derived from a vaccinia vaccine strain that has been engineered for 1) enhanced cancer targeting and 2) has been "armed" with the therapeutic transgene granulocytemacrophage colony stimulating factor (GM-CSF) to stimulate anti-tumoral immunity. Poxviruses have many ideal features for use as oncolytic agents. The development of oncolytic vaccinia viruses is supported by a large safety database accumulated in the smallpox eradication program. In addition, poxviruses have evolved unique capabilities for systemic spread through the blood that can be harnessed for the treatment of metastatic disease. JX-594 demonstrates a high degree of cancer selectivity and systemic efficacy by multiple mechanisms-of-action (MOAs) in preclinical testing. Data from Phase 1 and 2 clinical trials has confirmed that these features result in potent and systemic efficacy in patients with treatment refractory metastatic cancers.
    Current pharmaceutical biotechnology 07/2011; 13(9):1768-72. · 3.40 Impact Factor
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    Steve H Thorne
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    ABSTRACT: There has recently been resurgence in interest for the use of replication-selective (oncolytic) viruses for the treatment of cancers. This has been fueled by positive clinical data and the promise provided by next-generation vectors that are better targeted and display enhanced therapeutic potential. One factor that has led to more effective oncolytic vectors has been a greater appreciation of their immunotherapeutic potential. This is especially true for strains of vaccinia virus, where the capability for rapid and destructive spread through a target tissue makes this virus the ideal backbone for an oncolytic agent, while its known ability to produce a potent immune response makes it a powerful immunotherapeutic. Approaches to developing next-generation vectors that are capable of effectively harnessing both of these mechanisms of action are discussed here.
    Immunologic Research 06/2011; 50(2-3):286-93. · 2.96 Impact Factor
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    ABSTRACT: Tumor vaccines can induce robust immune responses targeting tumor antigens in the clinic, but antitumor effects have been disappointing. One reason for this is ineffective tumor infiltration of the cytotoxic T lymphocytes (CTLs) produced. Oncolytic viruses are capable of selectively replicating within tumor tissue and can induce a strong immune response. We therefore sought to determine whether these therapies could be rationally combined such that modulation of the tumor microenvironment by the viral therapy could help direct beneficial CTLs induced by the vaccine. As such, we examined the effects of expressing chemokines from oncolytic vaccinia virus, including CCL5 (RANTES), whose receptors are expressed on CTLs induced by different vaccines, including type-1-polarized dendritic cells (DC1). vvCCL5, an oncolytic vaccinia virus expressing CCL5, induced chemotaxis of lymphocyte populations in vitro and in vivo, and displayed improved safety in vivo. Interestingly, enhanced therapeutic benefits with vvCCL5 in vivo correlated with increased persistence of the viral agent exclusively within the tumor. When tumor-bearing mice were both vaccinated with DC1 and treated with vvCCL5 a further significant enhancement in tumor response was achieved which correlated with increased levels of tumor infiltrating lymphocytes. This approach therefore represents a novel means of combining biological therapies for cancer treatment.
    Molecular Therapy 01/2011; 19(4):650-7. · 7.04 Impact Factor
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    ABSTRACT: Vaccinia virus (VacV) enters mammalian cells, replicates extranuclearly, and produces virions that move to the cell surface along microtubules, fuse with the plasma membrane, and move from infected cells toward apposing cells on actin-filled membranous protrusions or actin tails. To form actin tails, cell-associated enveloped virions (CEV) require Abl and Src family tyrosine kinases. Furthermore, release of CEV from the cell requires Abl but not Src family tyrosine kinases and is blocked by imatinib mesylate (STI-571; Gleevec), an Abl family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Here we demonstrate that the Poxviridae family members monkeypox virus (MPX) and variola virus (VarV) use conserved mechanisms for actin motility and extracellular enveloped virion (EEV) release. Furthermore, we show that imatinib mesylate is effective in a mouse model of infection with VacV, whether delivered prophylactically or postinfection, and restricts spread of virions from the site of inoculation. While inhibitors of both Src and Abl family kinases, such as dasatinib (BMS-354825; Sprycel), are effective in limiting dissemination of VacV, VarV, and MPX in vitro, members of this class of drugs appear to have immunosuppressive effects in vivo that preclude their use as anti-infectives. Together, these data suggest a possible utility for imatinib mesylate in treating smallpox or MPX infections or complications associated with vaccination.
    Journal of Virology 10/2010; 85(1):21-31. · 5.08 Impact Factor
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    ABSTRACT: Current treatments of high-grade lymphoma often have curative potential, but unfortunately many patients relapse and develop therapeutic resistance. Thus, there remains a need for novel therapeutics that can target the residual cancer cells whose phenotypes are distinct from the bulk tumor and that are capable of reforming tumors from very few cells. Oncolytic viruses offer an approach to destroy tumors by multiple mechanisms, but they cannot effectively reach residual disease or micrometastases, especially within the lymphatic system. To address these limitations, we have generated immune cells infected with oncolytic viruses as a therapeutic strategy that can combine effective cellular delivery with synergistic tumor killing. In this study, we tested this approach against minimal disease states of lymphomas characterized by the persistence of cancer cells that display stem cell-like properties and resistance to conventional therapies. We found that the immune cells were capable of trafficking to and targeting residual cancer cells. The combination biotherapy used prevented relapse by creating a long-term, disease-free state, with acquired immunity to the tumor functioning as an essential mediator of this effect. Immune components necessary for this acquired immunity were identified. We further demonstrated that the dual biotherapy could be applied before or after conventional therapy. Our approach offers a potentially powerful new way to clear residual cancer cells, showing how restoring immune surveillance is critical for maintenance of a disease-free state.
    Cancer Research 10/2010; 70(23):9837-45. · 9.28 Impact Factor
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    ABSTRACT: Vaccinia immunization was pivotal to successful smallpox eradication. However, the early immune responses that distinguish poxvirus immunization from pathogenic infection remain unknown. To address this, we developed a strategy to map the activation of key signaling networks in vivo and applied this approach to define and compare the earliest signaling events elicited by immunizing (vaccinia) and lethal (ectromelia) poxvirus infections in mice. Vaccinia induced rapid TLR2-dependent responses, leading to IL-6 production, which then initiated STAT3 signaling in dendritic and T cells. In contrast, ectromelia did not induce TLR2 activation, and profound mouse strain-dependent responses were observed. In resistant C57BL/6 mice, the STAT1 and STAT3 pathways were rapidly activated, whereas in susceptible BALB/c mice, IL-6-dependent STAT3 activation did not occur. These data link early immune signaling events to infection outcome and suggest that activation of different pattern-recognition receptors early after infection may be important in determining vaccine efficacy.
    Cell host & microbe 08/2010; 8(2):174-85. · 13.02 Impact Factor
  • Padma Sampath, Steve H. Thorne
    08/2010: pages 119 - 140; , ISBN: 9780470626528
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    ABSTRACT: A major barrier to all oncolytic viruses (OVs) in clinical development is cellular innate immunity, which is variably active in a spectrum of human malignancies. To overcome the heterogeneity of tumor response, we combined complementary OVs that attack cancers in distinct ways to improve therapeutic outcome. Two genetically distinct viruses, vesicular stomatitis virus (VSV) and vaccinia virus (VV), were used to eliminate the risk of recombination. The combination was tested in a variety of tumor types in vitro, in immunodeficient and immunocompetent mouse tumor models, and ex vivo, in a panel of primary human cancer samples. We found that VV synergistically enhanced VSV antitumor activity, dependent in large part on the activity of the VV B18R gene product. A recombinant version of VSV expressing the fusion-associated small-transmembrane (p14FAST) protein also further enhanced the ability of VV to spread through an infected monolayer, resulting in a "ping pong" oncolytic effect wherein each virus enhanced the ability of the other to replicate and/or spread in tumor cells. Our strategy is the first example where OVs are rationally combined to utilize attributes of different OVs to overcome the heterogeneity of malignancies and demonstrates the feasibility of combining complementary OVs to improve therapeutic outcome.
    Molecular Therapy 03/2010; 18(5):888-95. · 7.04 Impact Factor
  • Steve H Thorne
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    ABSTRACT: The ability to externally regulate the expression or function of a gene product has proven to be a powerful tool in the study of proteins and disease in vitro, and more recently in transgenic animal models. The transfer of these technologies to regulate a therapeutic, adoptively transferred gene product in a clinical setting may provide a means to exert additional control over a large variety of therapies for many diseases, leading to increased safety and effectiveness. This could be applied to any biological therapy, including gene therapy, viral therapies, cellular therapies (such as immune cell therapies, stem cell therapies and bone marrow transplant), some vaccines and even organ transplant. A variety of systems have been used in a basic research setting to conditionally regulate the function of a protein, including control of transcription and mRNA stability, and the use of protein inhibitors. However, most of these have disadvantages for medical use, where a simple, specific, tunable, reversible and broadly applicable means to regulate protein function is needed. Recent advances in controlling the stability or function of proteins through the interaction of small-molecule effectors and fusion domains on the protein have raised the possibility that direct and highly specific external control of therapeutic protein function in humans will be feasible.
    Expert Reviews in Molecular Medicine 01/2010; 12:e2. · 6.62 Impact Factor
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    ABSTRACT: Bacterial targeting of tumours is an important anti-cancer strategy. We previously showed that strain SL7838 of Salmonella typhimurium targets and kills cancer cells. Whether NO generation by the bacteria has a role in SL7838 lethality to cancer cells is explored. This bacterium has the mechanism for generating NO, but also for decomposing it. Mechanism underlying Salmonella typhimurium tumour therapy was investigated through in vitro and in vivo studies. NO measurements were conducted either by chemical assays (in vitro) or using Biosensors (in vivo). Cancer cells cytotoxic assay were done by using MTS. Bacterial cell survival and tumour burden were determined using molecular imaging techniques. SL7838 generated nitric oxide (NO) in anaerobic cell suspensions, inside infected cancer cells in vitro and in implanted 4T1 tumours in live mice, the last, as measured using microsensors. Thus, under these conditions, the NO generating pathway is more active than the decomposition pathway. The latter was eliminated, in strain SL7842, by the deletion of hmp- and norV genes, making SL7842 more proficient at generating NO than SL7838. SL7842 killed cancer cells more effectively than SL7838 in vitro, and this was dependent on nitrate availability. This strain was also ca. 100% more effective in treating implanted 4T1 mouse tumours than SL7838. NO generation capability is important in the killing of cancer cells by Salmonella strains.
    BMC Cancer 01/2010; 10:146. · 3.33 Impact Factor
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    ABSTRACT: An early reaction of CD4(+) T lymphocytes to Ag is the production of cytokines, notably IL-2. To detect cytokine-dependent responses, naive Ag-specific T cells were stimulated in vivo and the presence of phosphorylated STAT5 molecules was used to identify the cell populations responding to IL-2. Within hours of T cell priming, IL-2-dependent STAT5 phosphorylation occurred primarily in Foxp3(+) regulatory T cells. In contrast, the Ag-specific T cells received STAT5 signals only after repeated Ag exposure or memory differentiation. Regulatory T cells receiving IL-2 signals proliferated and developed enhanced suppressive activity. These results indicate that one of the earliest events in a T cell response is the activation of endogenous regulatory cells, potentially to prevent autoimmunity.
    The Journal of Immunology 08/2009; 183(1):332-9. · 5.52 Impact Factor

Publication Stats

824 Citations
298.06 Total Impact Points

Institutions

  • 2008–2014
    • University of Pittsburgh
      • • Department of Surgery
      • • Division of Surgical Oncology
      Pittsburgh, Pennsylvania, United States
  • 2005–2011
    • Jennerex Biotherapeutics
      San Francisco, California, United States
  • 2007–2010
    • Stanford Medicine
      • Department of Microbiology and Immunology
      Stanford, California, United States
  • 2004–2009
    • Stanford University
      • • Department of Microbiology and Immunology
      • • Department of Medicine
      Stanford, CA, United States