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Mi Kyung Kim,
Caroline J. Breitbach,
Anne Moon,
Jeong Heo,
Yu Kyoung Lee,
Mong Cho,
Jun Woo Lee,
Seong-Geun Kim,
Dae Hwan Kang, John C. Bell,
Byeong Ho Park,
David H. Kirn,
Tae-Ho Hwang
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ABSTRACT: Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec–treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody–mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.
Science translational medicine 05/2013; 5(185):185ra63. · 7.80 Impact Factor
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Jeong Heo,
Tony Reid,
Leyo Ruo,
Caroline J Breitbach,
Steven Rose,
Mark Bloomston,
Mong Cho,
Ho Yeong Lim,
Hyun Cheol Chung,
Chang Won Kim, [......],
Mi Kyeong Kim,
Manijeh Daneshmand,
Kara Dubois,
Lara Longpre,
Minhtran Ngo,
Cliona Rooney, John C Bell,
Byung-Geon Rhee,
Richard Patt,
Tae-Ho Hwang & David H Kirn
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ABSTRACT: Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n = 30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P = 0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.
Nature Medicine 02/2013; · 22.46 Impact Factor
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Judith Caroline J Breitbach,
Rozanne Arulanandam,
Naomi De Silva,
Steve H Thorne,
Richard Patt,
Manijeh Daneshmand,
Anne Moon,
Carolina Ilkow,
James Burke,
Tae-Ho Hwang,
Jeong Heo,
Mong Cho,
Hannah Chen,
Fernando A Angarita,
Christina Addison,
J Andrea McCart, John C Bell,
David H Kirn
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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; · 7.86 Impact Factor
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Byram W Bridle,
Lan Chen,
Chantal G Lemay,
Jean-Simon Diallo,
Jonathan Pol,
Andrew Nguyen,
Alfredo Capretta,
Rongqiao He,
Jonathan L Bramson, John C Bell,
Brian D Lichty,
Yonghong Wan
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ABSTRACT: Histone deacetylase inhibitors (HDACi) can modulate innate antiviral responses and render tumors more susceptible to oncolytic viruses (OVs); however, their effects on adaptive immunity in this context are largely unknown. Our present study reveals an unexpected property of the HDACi MS-275 that enhances viral vector-induced lymphopenia leading to selective depletion of bystander lymphocytes and regulatory T cells while allowing expansion of antigen-specific secondary responses. Coadministration of vaccine plus drug during the boosting phase focuses the immune response on the tumor by suppressing the primary immune response against the vaccine vector and enhancing the secondary response against the tumor antigen. Furthermore, improvement of T cell functionality was evident suggesting that MS-275 can orchestrate a complex array of effects that synergize immunotherapy and viral oncolysis. Surprisingly, while MS-275 dramatically enhanced efficacy, it suppressed autoimmune pathology, profoundly improving the therapeutic index.Molecular Therapy (2013); doi:10.1038/mt.2012.265.
Molecular Therapy 01/2013; · 6.87 Impact Factor
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Markus J V Vähä-Koskela,
Fabrice Le Boeuf,
Chantal Lemay,
Naomi De Silva,
Jean-Simon Diallo,
Julie Cox,
Michelle Becker,
Youngmin Choi,
Abhirami Ananth,
Clara Sellers,
Sophie Breton,
Dominic Roy,
Theresa Falls,
Jan Brun,
Akseli Hemminki,
Ari Hinkkanen, John C Bell
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ABSTRACT: Attenuated Semliki Forest virus (SFV) may be suitable for targeting malignant glioma due to its natural neurotropism, but its replication in brain tumor cells may be restricted by innate antiviral defenses. We attempted to facilitate SFV replication in glioma cells by combining it with vaccinia virus which is capable of antagonizing such defenses. Surprisingly, we found parenchymal mouse brain tumors to be refractory to either virus. Also, vaccinia virus appears sensitive to SFV-induced antiviral interference.
Journal of Virology 12/2012; · 5.40 Impact Factor
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ABSTRACT: OBJECTIVES:: To determine whether the postoperative hypercoagulable state is responsible for the increase in metastases observed after surgery. BACKGROUND:: Surgery precipitates a hypercoagulable state and increases the formation of cancer metastases in animal models. Coagulation promotes metastases by facilitating the formation of microthrombi around tumor cell emboli (TCE), thereby inhibiting natural killer (NK) cell-mediated destruction. METHODS:: Mice underwent surgery preceded by tumor cell inoculation to establish pulmonary metastases in the presence or absence of various perioperative anticoagulants. Pulmonary TCE were quantified and characterized using fluorescently labeled fibrinogen and platelets. The role of NK cells was evaluated by repeating these experiments after antibody depletion in a genetically deficient strain and by adoptively transferring NK cells into NK-deficient mice. RESULTS:: Surgery resulted in a consistent and significant increase in metastases while a number of different anticoagulants and platelet depletion attenuated this effect. Impaired clearance of TCE from the lungs associated with an increase in peritumoral fibrin and platelet clot formation was observed in surgically stressed mice, but not in control mice or mice that received perioperative anticoagulation. The increase in TCE survival conferred by surgery and inhibited by perioperative anticoagulation was eliminated by the immunological or genetic depletion of NK cells. Adoptive transfer experiment confirms that surgery impairs NK cell function. CONCLUSIONS:: Surgery promotes the formation of fibrin and platelet clots around TCE, thereby impairing NK cell-mediated tumor cell clearance, whereas perioperative anticoagulation attenuates this effect. Therapeutic interventions aimed at reducing peritumoral clot formation and enhancing NK cell function in the perioperative period will have important clinical implications in attenuating metastatic disease after cancer surgery.
Annals of surgery 10/2012; · 7.90 Impact Factor
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Lee-Hwa Tai,
Christiano Tanese de Souza,
Simon Belanger,
Lundi Ly,
Almohanad A Alkayyal,
Jiqing Zhang,
Julia L Rintoul,
Abhirami A Ananth,
Tiffany Lam,
Caroline J Breitbach,
Theresa J Falls,
David H Kirn, John C Bell,
Andrew P Makrigiannis,
Rebecca A Auer
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ABSTRACT: Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice compared to mice who received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and MDSC populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic ORF and vaccinia virus can reverse NK cell suppression which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity and we demonstrate for the first time that oncolytic vaccinia virus markedly increases NK cell activity in cancer patients. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients.
Cancer Research 10/2012; · 7.86 Impact Factor
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ABSTRACT: Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.
Nature Biotechnology 07/2012; 30(7):658-70. · 29.50 Impact Factor
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Chantal G Lemay,
Julia L Rintoul,
Agnieszka Kus,
Jennifer M Paterson,
Vanessa Garcia,
Theresa J Falls,
Lisa Ferreira,
Byram W Bridle,
David P Conrad,
Vera A Tang, [......],
Rozanne Arulanandam,
Fabrice Le Boeuf,
Kenneth Garson,
Barbara C Vanderhyden,
David F Stojdl,
Brian D Lichty,
Harold L Atkins,
Kelley A Parato, John C Bell,
Rebecca C Auer
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ABSTRACT: Treatment of permissive tumors with the oncolytic virus (OV) VSV-Δ51 leads to a robust antitumor T-cell response, which contributes to efficacy; however, many tumors are not permissive to in vivo treatment with VSV-Δ51. In an attempt to channel the immune stimulatory properties of VSV-Δ51 and broaden the scope of tumors that can be treated by an OV, we have developed a potent oncolytic vaccine platform, consisting of tumor cells infected with VSV-Δ51. We demonstrate that prophylactic immunization with this infected cell vaccine (ICV) protected mice from subsequent tumor challenge, and expression of granulocyte-monocyte colony stimulating factor (GM-CSF) by the virus (VSVgm-ICV) increased efficacy. Immunization with VSVgm-ICV in the VSV-resistant B16-F10 model induced maturation of dendritic and natural killer (NK) cell populations. The challenge tumor is rapidly infiltrated by a large number of interferon γ (IFNγ)-producing T and NK cells. Finally, we demonstrate that this approach is robust enough to control the growth of established tumors. This strategy is broadly applicable because of VSV's extremely broad tropism, allowing nearly all cell types to be infected at high multiplicities of infection in vitro, where the virus replication kinetics outpace the cellular IFN response. It is also personalized to the unique tumor antigen(s) displayed by the cancer cell.
Molecular Therapy 07/2012; 20(9):1791-9. · 6.87 Impact Factor
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ABSTRACT: BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 5th most common cancer worldwide. Locally advanced HNSCC are treated with either radiation or chemo-radiotherapy, but still associated with high mortality rate, underscoring the need to develop novel therapies. Oncolytic viruses have been garnering increasing interest as anti-cancer agents due to their preferential killing of transformed cells. In this study, we evaluated the therapeutic potential of mutant vesicular stomatitis virus (VSVdelta51) against the human hypopharyngeal FaDu tumour model in vitro and in vivo. METHODS: MTS assay was utilized to assess cell viability. Flow cytometry and Caspase 3/7 activation was utilized to assess apoptosis. In vivo studies were conducted using CD-1 nude mice. Fluorescence microscopy was utilized to assess viral replication in vitro and in vivo. RESULTS: Our data demonstrated high toxicity of the virus against FaDu cells in vitro, which was associated with induction of apoptosis. In vivo, systemic injection of 1x109 pfu had minimal effect on tumour growth; however, when combined with two doses of ionizing radiation (IR; 5 Gy each) or a single injection of the vascular disrupting agent (ZD6216), the virus exhibited profound suppression of tumour growth, which translated to a prolonged survival in the treated mice. Concordantly, VSVdelta51 combined with ZD6216 led to a significant increase in viral replication in these tumours. CONCLUSIONS: Our data suggest that the combinations of VSVdelta51 with either IR or ZD6216 are potentially novel therapeutic opportunities for HNSCC.
Cancer Cell International 06/2012; 12(1):27. · 1.97 Impact Factor
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Julia L Rintoul,
Chantal G Lemay,
Lee-Hwa Tai,
Marianne M Stanford,
Theresa J Falls,
Christiano T de Souza,
Byram W Bridle,
Manijeh Daneshmand,
Pamela S Ohashi,
Yonghong Wan,
Brian D Lichty,
Andrew A Mercer,
Rebecca C Auer,
Harold L Atkins, John C Bell
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ABSTRACT: Replicating viruses for the treatment of cancer have a number of advantages over traditional therapeutic modalities. They are highly targeted, self-amplifying, and have the added potential to act as both gene-therapy delivery vehicles and oncolytic agents. Parapoxvirus ovis or Orf virus (ORFV) is the prototypic species of the Parapoxvirus genus, causing a benign disease in its natural ungulate host. ORFV possesses a number of unique properties that make it an ideal viral backbone for the development of a cancer therapeutic: it is safe in humans, has the ability to cause repeat infections even in the presence of antibody, and it induces a potent T(h)-1-dominated immune response. Here, we show that live replicating ORFV induces an antitumor immune response in multiple syngeneic mouse models of cancer that is mediated largely by the potent activation of both cytokine-secreting, and tumoricidal natural killer (NK) cells. We have also highlighted the clinical potential of the virus by demonstration of human cancer cell oncolysis including efficacy in an A549 xenograft model of cancer.
Molecular Therapy 01/2012; 20(6):1148-57. · 6.87 Impact Factor
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Future Oncology 01/2012; 8(1):1-4. · 3.16 Impact Factor
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Kelley A Parato,
Caroline J Breitbach,
Fabrice Le Boeuf,
Jiahu Wang,
Chris Storbeck,
Carolina Ilkow,
Jean-Simon Diallo,
Theresa Falls,
Joseph Burns,
Vanessa Garcia,
Femina Kanji,
Laura Evgin,
Kang Hu,
Francois Paradis,
Shane Knowles,
Tae-Ho Hwang,
Barbara C Vanderhyden,
Rebecca Auer,
David H Kirn, John C Bell
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ABSTRACT: Oncolytic viruses are generally designed to be cancer selective on the basis of a single genetic mutation. JX-594 is a thymidine kinase (TK) gene-inactivated oncolytic vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and lac-Z transgenes that is designed to destroy cancer cells through replication-dependent cell lysis and stimulation of antitumoral immunity. JX-594 has demonstrated a favorable safety profile and reproducible tumor necrosis in a variety of solid cancer types in clinical trials. However, the mechanism(s) responsible for its cancer-selectivity have not yet been well described. We analyzed the replication of JX-594 in three model systems: primary normal and cancer cells, surgical explants, and murine tumor models. JX-594 replication, transgene expression, and cytopathic effects were highly cancer-selective, and broad spectrum activity was demonstrated. JX-594 cancer-selectivity was multi-mechanistic; replication was activated by epidermal growth factor receptor (EGFR)/Ras pathway signaling, cellular TK levels, and cancer cell resistance to type-I interferons (IFNs). These findings confirm a large therapeutic index for JX-594 that is driven by common genetic abnormalities in human solid tumors. This appears to be the first description of multiple selectivity mechanisms, both inherent and engineered, for an oncolytic virus. These findings have implications for oncolytic viruses in general, and suggest that their cancer targeting is a complex and multifactorial process.
Molecular Therapy 12/2011; 20(4):749-758. · 6.87 Impact Factor
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ABSTRACT: High-risk carcinogenic subtypes of human papilloma virus (HPV) are associated with the development of squamous cell carcinomas of the cervix (CC) and a subset of head and neck (HNSCC). Recurrent metastatic diseases of these sites display a dismal prognosis. Therefore, there is an urgent need to uncover innovative therapeutic strategies in this clinical setting. Oncolytic viruses, including vesicular stomatitis virus (VSV), were identified due to their ability to specifically target tumor cells that generally display defects in interferon (IFN) signaling. HPV expressed proteins can inhibit IFN signaling; therefore, HPV-infected cells may be particularly sensitive to VSV oncolysis. In this study, we evaluated the sensitivity of four CC (HPV+) and four HNSCC (HPV-) derived cell lines to VSV oncolysis. Interestingly, the CC cell lines were consistently more sensitive to VSV cytotoxicity than the HNSCC cell lines tested. Exogenous IFN addition or infection with two attenuated VSV variants that are more susceptible to IFN inhibition failed to attenuate VSV oncolysis in hypersensitive CC cell lines. Furthermore, the expression of HPV-E6, that inhibits IFN receptor signaling, in the VSV-resistant HNSCC cell line SCC25 attenuated VSV-induced IFN response and significantly enhanced VSV cytotoxicity. Finally, differential VSV infection and replication was confirmed in xenograft murine tumor models and explant tumor tissues from two patients with CC. Taken together, these results demonstrate that HPV-infected cells are susceptible to oncolytic virus therapy and that this approach may represent a novel therapeutic approach in HPV positive CC and HNSCC patients.
International Journal of Cancer 12/2011; 131(3):E204-15. · 5.44 Impact Factor
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Ping Jun Zhu,
Wei Huang,
Djanenkhodja Kalikulov,
Jong W Yoo,
Andon N Placzek,
Loredana Stoica,
Hongyi Zhou, John C Bell,
Michael J Friedlander,
Krešimir Krnjević,
Jeffrey L Noebels,
Mauro Costa-Mattioli
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ABSTRACT: The double-stranded RNA-activated protein kinase (PKR) was originally identified as a sensor of virus infection, but its function in the brain remains unknown. Here, we report that the lack of PKR enhances learning and memory in several behavioral tasks while increasing network excitability. In addition, loss of PKR increases the late phase of long-lasting synaptic potentiation (L-LTP) in hippocampal slices. These effects are caused by an interferon-γ (IFN-γ)-mediated selective reduction in GABAergic synaptic action. Together, our results reveal that PKR finely tunes the network activity that must be maintained while storing a given episode during learning. Because PKR activity is altered in several neurological disorders, this kinase presents a promising new target for the treatment of cognitive dysfunction. As a first step in this direction, we show that a selective PKR inhibitor replicates the Pkr(-/-) phenotype in WT mice, enhancing long-term memory storage and L-LTP.
Cell 12/2011; 147(6):1384-96. · 32.40 Impact Factor
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Caroline J Breitbach,
James Burke,
Derek Jonker,
Joe Stephenson,
Andrew R Haas,
Laura Q M Chow,
Jorge Nieva,
Tae-Ho Hwang,
Anne Moon,
Richard Patt, [......],
Sara Cvancic,
Terri Robertson,
Ji-Eun Je,
Yeon-Sook Lee,
Kelley Parato,
Jean-Simon Diallo,
Aaron Fenster,
Manijeh Daneshmand, John C Bell,
David H Kirn
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ABSTRACT: The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.
Nature 09/2011; 477(7362):99-102. · 36.28 Impact Factor
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Tae-Ho Hwang,
Anne Moon,
James Burke,
Antoni Ribas,
Joe Stephenson,
Caroline J Breitbach,
Manijeh Daneshmand,
Naomi De Silva,
Kelley Parato,
Jean-Simon Diallo,
Yeon-Sook Lee,
Ta-Chiang Liu, John C Bell,
David H Kirn
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ABSTRACT: JX-594 is a targeted and granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In order to study the mechanisms-of-action (MOA) of JX-594 in humans, a mechanistic proof-of-concept clinical trial was performed at a low dose equivalent to ≤10% of the maximum-tolerated dose (MTD) in other clinical trials. Ten patients with previously treated stage IV melanoma were enrolled. Tumors were injected weekly for up to nine total treatments. Blood samples and tumor biopsies were analyzed for evidence of transgene activity, virus replication, and immune stimulation. The β-galactosidase (β-gal) transgene was expressed in all patients as evidenced by antibody induction. Six patients had significant induction of GM-CSF-responsive white blood cell (WBC) subsets such as neutrophils (25-300% increase). JX-594 replication and subsequent shedding into blood was detectable in five patients after cycles 1-9. Tumor biopsies demonstrated JX-594 replication, perivascular lymphocytic infiltration, and diffuse tumor necrosis. Mild flu-like symptoms were the most common adverse events. In sum, JX-594 replication, oncolysis, and expression of both transgenes were demonstrated; replication was still evident after multiple cycles. These findings have implications for further clinical development of JX-594 and other transgene-armed oncolytic viruses.
Molecular Therapy 07/2011; 19(10):1913-22. · 6.87 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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ABSTRACT: For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers.
Molecular Therapy 06/2011; 19(6):1008-16. · 6.87 Impact Factor
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Caroline J Breitbach,
Naomi S De Silva,
Theresa J Falls,
Usaf Aladl,
Laura Evgin,
Jennifer Paterson,
Yang Yang Sun,
Dominic G Roy,
Julia L Rintoul,
Manijeh Daneshmand,
Kelley Parato,
Marianne M Stanford,
Brian D Lichty,
Aaron Fenster,
David Kirn,
Harold Atkins, John C Bell
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ABSTRACT: Oncolytic viruses (OVs) have been engineered or selected for cancer cell-specific infection however, we have found that following intravenous administration of vesicular stomatitis virus (VSV), tumor cell killing rapidly extends far beyond the initial sites of infection. We show here for the first time that VSV directly infects and destroys tumor vasculature in vivo but leaves normal vasculature intact. Three-dimensional (3D) reconstruction of infected tumors revealed that the majority of the tumor mass lacks significant blood flow in contrast to uninfected tumors, which exhibit relatively uniform perfusion. VSV replication in tumor neovasculature and spread within the tumor mass, initiates an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels. Within 6 hours of intravenous administration of VSV and continuing for at least 24 hours, we observed the initiation of blood clots within the tumor vasculature whereas normal vasculature remained clot free. Blocking blood clot formation with thrombin inhibitors prevented tumor vascular collapse. Our results demonstrate that the therapeutic activity of an OV can go far beyond simple infection and lysis of malignant cells.
Molecular Therapy 03/2011; 19(5):886-94. · 6.87 Impact Factor
