Delivery Of Oncolytic Viruses Research Articles

Lymphokine‐activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus-induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine-activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL-12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune-mediated tumor cell killing.What’s new?Oncolytic viruses (OVs) specifically infect and kill tumor cells. In this study, the authors began to examine whether intraperitoneal delivery of an OV could be effective against ovarian cancer. They found that, while the virus does kill ovarian-cancer cells in vitro, this effect is blocked when ascites fluid is added. Cytotoxicity can be restored, however, by using a combination of lymphokine-activated killer and dendritic cells (LAKDC) as carriers, which protect the virus from neutralizing antibodies in the ascites. The LAKDC combination may also support subsequent adaptive immune priming.

The Efficacy Versus Toxicity Profile of Combination Virotherapy and TLR Immunotherapy Highlights the Danger of Administering TLR Agonists to Oncolytic Virus-treated Mice

Injection of oncolytic vesicular stomatitis virus (VSV) into established B16ova melanomas results in tumor regression, in large part by inducing innate immune reactivity against the viral infection, mediated by MyD88- and type III interferon (IFN)-, but not TLR-4-, signaling. We show here that intratumoral (IT) treatment with lipopolysaccharide (LPS), a TLR-4 agonist, significantly enhanced the local therapy induced by VSV by combining activation of different innate immune pathways. Therapy was further enhanced by co-recruiting a potent antitumor, adaptive T-cell response by using a VSV engineered to express the ovalbumin tumor-associated antigen ova, in combination with LPS. However, the combination of IT LPS with systemically delivered VSV resulted in rapid morbidity and mortality in the majority of mice. Decreasing the intravenous (IV) dose of VSV to levels at which toxicity was ameliorated did not enhance therapy compared with IT LPS alone. Toxicity of the systemic VSV + IT LPS regimen was associated with rapidly elevated levels of serum tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, which neither systemic VSV, nor IT LPS, alone induced. These data show that therapy associated with direct IT injections of oncolytic viruses can be significantly enhanced by combination with agonists of innate immune activation pathways, which are not themselves activated by the virus alone. Importantly, they also highlight possible, unforeseen dangers of combination therapies in which an immunotherapy, even delivered locally at the tumor site, may systemically sensitize the patient to a cytokine shock-like response triggered by IV delivery of oncolytic virus.

Vitamin D3-Inducible Mesenchymal Stem Cell-Based Delivery of Conditionally Replicating Adenoviruses Effectively Targets Renal Cell Carcinoma and Inhibits Tumor Growth

Cell-based carriers were recently exploited as a tumor-targeting tool to improve systemic delivery of oncolytic viruses for cancer therapy. However, the slow clearance of carrier cells from normal organs indicates the need for a controllable system which allows viral delivery only when the carrier cells reach the tumor site. In this study, we sought to develop a pharmaceutically inducible cell-based oncolytic adenovirus delivery strategy for effective targeting and treatment of renal cell carcinoma (RCC), which is one of the most malignant tumor types with an unfavorable prognosis. Herein, we demonstrated the intrinsic tumor homing property of human bone marrow-derived mesenchymal stem cells (hMSCs) to specifically localize primary and metastatic RCC tumors after systemic administration in a clinically relevant orthotopic animal model. The platelet derived growth factor AA (PDGF-AA) secreted from RCC was identified as a chemoattractant responsible for the recruitment of hMSCs. Like endogenous osteocalcin whose barely detectable level of expression was dramatically induced by vitamin D(3), the silenced replication of human osteocalcin promoter-directed Ad-hOC-E1 oncolytic adenoviruses loaded in hMSCs was rapidly activated, and the released oncolytic adenoviruses sequentially killed cocultured RCC cells upon vitamin D(3) exposure. Moreover, the systemic treatment of RCC tumor-bearing mice with hMSC cell carriers loaded with Ad-hOC-E1 had very limited effects on tumor growth, but the loaded hMSCs combined with vitamin D(3) treatment induced effective viral delivery to RCC tumors and significant tumor regression. Therapeutic effects of hMSC-based Ad-hOC-E1 delivery were confirmed to be significantly greater than those of injection of carrier-free Ad-hOC-E1. Our results presented the first preclinical demonstration of a novel controllable cell-based gene delivery strategy that combines the advantages of tumor tropism and vitamin D(3)-regulatable human osteocalcin promoter-directed gene expression of hMSCs to improve oncolytic virotherapy for advanced RCC.

Abstract 5661: Pharmaceutically controlled replication of adenoviruses in mesenchymal stem cell-based cell carriers improves oncolytic virotherapy for advanced human renal cell carcinoma

Abstract Cell-based carriers were recently exploited as a tumor-targeting tool to improve systemic delivery of oncolytic viruses for cancer therapy. However, the slow clearance of carrier cells from normal organs indicates the need for a controllable system which allows viral delivery only when the carrier cells reach the tumor site. In this communication, we sought to develop a pharmaceutically-inducible cell-based oncolytic adenovirus delivery strategy for effective targeting and treatment of renal cell carcinoma (RCC), which is one of the most malignant tumor types with an unfavorable prognosis. Herein, we demonstrated the intrinsic tumor homing property of human bone marrow-derived mesenchymal stem cells (hMSCs) to specifically localize primary and metastatic RCC tumors after systemic administration in a clinically relevant orthotopic animal model. PDGF-AA secreted from RCC was identified as a chemoattractant responsible for the recruitment of hMSCs. Like endogenous osteocalcin whose barely detectable level of expression was dramatically induced by vitamin D3, the silenced replication of human osteocalcin promoter-directed Ad-hOC-E1 oncolytic adenoviruses loaded in hMSCs was rapidly activated and the released viral progenies sequentially killed co-cultured RCC cells upon vitamin D3 exposure. Moreover, systemic treatment of RCC tumor-bearing mice with Ad-hOC-E1-loaded hMSCs had very limited effect on tumor growth, but when it combined with vitamin D3 treatment induced effective viral delivery to RCC tumors and significant tumor regression. Therapeutic effects of hMSC-based Ad-hOC-E1 delivery were confirmed to be significantly greater than those of injection of carrier-free Ad-hOC-E1. Our results presented the first pre-clinical demonstration of a novel controllable cell-based gene delivery strategy that combines the advantages of tumor tropism and vitamin D3-regulatable human osteocalcin promoter-directed gene expression of hMSCs to improve oncolytic virotherapy for advanced RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5661. doi:1538-7445.AM2012-5661

Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles

Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high. There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy. A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses.

Photodynamic therapy augments the efficacy of oncolytic vaccinia virus against primary and metastatic tumours in mice

Background:Therapies targeted towards the tumour vasculature can be exploited for the purpose of improving the systemic delivery of oncolytic viruses to tumours. Photodynamic therapy (PDT) is a clinically approved treatment for cancer that is known to induce potent effects on tumour vasculature. In this study, we examined the activity of PDT in combination with oncolytic vaccinia virus (OVV) against primary and metastatic tumours in mice.Methods:The effect of 2-[1-hexyloxyethyl-]-2-devinyl pyropheophorbide-a (HPPH)-sensitised-PDT on the efficacy of oncolytic virotherapy was investigated against subcutaneously implanted syngeneic murine NXS2 neuroblastoma and human FaDu head and neck squamous cell carcinoma xenografts in nude mice. Treatment efficacy was evaluated by monitoring tumour growth and survival. The effects of combination treatment on vascular function were examined using magnetic resonance imaging (MRI) and immunohistochemistry, whereas viral replication in tumour cells was analysed by a standard plaque assay. Normal tissue phototoxicity following PDT-OV treatment was studied using the mouse foot response assay.Results:Combination of PDT with OVV resulted in inhibition of primary and metastatic tumour growth compared with either monotherapy. PDT-induced vascular disruption resulted in higher intratumoural viral titres compared with the untreated tumours. Five days after delivery of OVV, there was a loss of blood flow to the interior of tumour that was associated with infiltration of neutrophils. Administration of OVV did not result in any additional photodynamic damage to normal mouse foot tissue.Conclusion:These results provide evidence into the usefulness of PDT as a means of enhancing intratumoural replication and therapeutic efficacy of OV.

Cell-based delivery of oncolytic viruses

Oncolytic viruses,a novel class of virus vectors,which selectively replicate only in tumor cells,have excellent tumor targeting and good tansfection efficiency.Many oncolytic viruses have apparent curative effect when administered intratumorally.However,the host immune system remains a critical obstacle to systemic administration of virotherapeutics.It appears that cell-based delivery of oncolytic viruses could offer one solution to this critical problem,which provides a new platform to the biological therapy of cancer. Key words: Oncolytic viruses ; Neoplasms ; Therapy ;

Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway

Tumour Necrosis Factor alpha (TNF) is a pleiotropic pro-inflammatory cytokine with known vascular permeabilising activity. It is employed during isolated limb perfusion to enhance delivery of chemotherapeutic drugs into tumour tissue. The use of conditionally-replicating lytic viruses, so called ‘oncolytic virotherapy’, provides a new approach to cancer treatment that is currently limited by the low efficiency of extravasation of viral particles into tumours. We report here evidence that TNF significantly enhances the delivery of virus particles through the endothelial layer to allow access to tumour cells both in vitro and in vivo. Intravenous administration of TNF resulted in a 3- to 6-fold increase in EL4 tumour uptake of Evans Blue/Albumin, adenovirus and long-circulating polymer coated adenovirus. Interestingly, endothelial permeabilisation could be suppressed in vitro and in vivo by Y-27632, a Rho kinase inhibitor, without inhibiting viral infection. These data indicate that TNF can enhance the delivery of virus particles into tumours through a Rho A/Rho kinase dependent mechanism and may be a valuable strategy for increasing the delivery of oncolytic viruses and other therapeutic agents.

Abstract 4145: “Real-time” monitoring of oncolytic viral delivery to solid tumors using contrast-enhanced computed tomography

Abstract RATIONALE: The inability to deliver viruses homogeneously throughout solid tumors is a universal obstacle encountered in oncolytic virotherapy. The initial intratumoral viral dispersion volume is a critical determinant of virotherapy efficacy, and depends not only on the number of infected cells, but also on the spatial distribution of the infected cells. In this study, we determined the feasibility and usefulness of monitoring the initial intratumoral delivery of oncolytic viruses to solid tumors using contrast-enhanced computed tomography (CT). EXPERIMENTAL PROCEDURES: Human BxPC-3 pancreatic tumor xenografts were established in nude mice. An engineered oncolytic measles virus expressing the sodium iodide symporter reporter (MV-NIS) was mixed with a 1:10 dilution of Omnipaque-300 contrast material and injected directly into mouse tumors. Mice were imaged with micro-CT immediately pre and post-injection of the virus + Omnipaque solution and on day 3 post-injection with 99mTcO4 micro-SPECT/CT. Tumors were harvested immediately after micro-SPECT/CT imaging for autoradiography and immunistochemistry analysis of radioactivity uptake and viral infection. Linear regression and Spearman correlation analyses were performed to determine the relationship between intratumoral contrast enhancement and subsequent intratumoral viral infection. RESULTS: This dilution of Omnipaque was found to have no effect on viral infectivity or cell viability in vitro, yet was more than adequate for CT imaging of the virus + Omnipaque injectate distribution following intratumoral injection. Ex vivo autoradiography and immunohistochemistry confirmed a strong correlation between intratumoral CT contrast enhancement, SPECT activity, viral infection, and sodium iodide symporter activity. CONCLUSIONS: This injection method is translatable to the clinic and should allow optimization of intratumoral injection in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4145. doi:10.1158/1538-7445.AM2011-4145

Active Adenoviral Vascular Penetration by Targeted Formation of Heterocellular Endothelial–epithelial Syncytia

The endothelium imposes a structural barrier to the extravasation of systemically delivered oncolytic adenovirus (Ad). Here, we introduced a transendothelial route of delivery in order to increase tumor accumulation of virus particles (vp) beyond that resulting from convection-dependent extravasation alone. This was achieved by engineering an Ad encoding a syncytium-forming protein, gibbon ape leukemia virus (GALV) fusogenic membrane glycoprotein (FMG). The expression of GALV was regulated by a hybrid viral enhancer-human promoter construct comprising the human cytomegalovirus (CMV) immediate-early enhancer and the minimal human endothelial receptor tyrosine kinase promoter (“eTie1”). Endothelial cell-selectivity of the resulting Ad-eTie1-GALV vector was demonstrated by measuring GALV mRNA transcript levels. Furthermore, Ad-eTie1-GALV selectively induced fusion between infected endothelial cells and uninfected epithelial cells in vitro and in vivo, allowing transendothelial virus penetration. Heterofusion of infected endothelium to human embryonic kidney 293 (HEK 293) cells, in mixed in vitro cultures or in murine xenograft models, permitted fusion-dependent transactivation of the replication-deficient Ad-eTie1-GALV, due to enabled access to viral E1 proteins derived from the HEK 293 cytoplasm. These data provide evidence to support our proposed use of GALV to promote Ad penetration through tumor-associated vasculature, an approach that may substantially improve the efficiency of systemic delivery of oncolytic viruses to disseminated tumors.

Oncolytic vesicular stomatitis virus administered by isolated limb perfusion suppresses osteosarcoma growth

A significant limitation to oncolytic virotherapy in vivo is the lack of a clinically relevant means of delivering the virus. We evaluated the oncolytic activity of vesicular stomatitis virus (VSV) in human osteosarcoma cells and explored isolated limb perfusion (ILP) as a novel oncolytic virus delivery system to extremity sarcoma in immune-competent rats. Human and rat osteosarcoma cells transduced with rVSV-lacZ uniformly expressed β-gal. VSV was fully capable of replicating its RNA genome in all osteosarcoma cell lines, and efficiently killed them in time- and dose-dependent manners, whereas normal bone marrow stromal cells were refractory to the virus. VSV delivered by ILP inhibited growth of osteosarcoma xenografts more potently than that injected intravenously and intratumorally in the hind limb of immune-competent rats. Histopathological sections of tumor lesions treated by ILP-delivered VSV showed positive for VSV-G protein. There were no VSV-G expressions in perfused leg muscle, nonperfused leg muscle, brain, lung, and liver in VSV-treated rats. Our findings show efficient VSV gene expression and replication in osteosarcoma cells, suggesting that osteosarcoma may be a promising target for oncolytic virotherapy with VSV. Furthermore, we firstly showed that ILP of VSV against extremity sarcoma caused antitumor activity.

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.

37. Insect Cell Carriers for Systemic Delivery of Oncolytic Viruses

37. Insect Cell Carriers for Systemic Delivery of Oncolytic Viruses

Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice.

Clinical trials of oncolytic virotherapy have shown low toxicity and encouraging signs of efficacy. However, it remains critically important to develop methods for systemic viral delivery if such therapies are to be clinically implemented to treat established tumors. In this respect, much effort is being focused on combining oncolytic viruses with standard treatment modalities such as inhibitors of VEGF165 (an alternatively spliced isoform of VEGF-A) signaling, which are widely used to treat several different cancers. Here, we have demonstrated that combining VEGF165 inhibitors with systemic delivery of oncolytic viruses leads to substantial regression and cure of established tumors in immunocompetent mice. We have shown that manipulating VEGF165-mediated signaling by administering VEGF165 to mice harboring mouse melanoma cells that do not express VEGF165 and by administering a VEGF inhibitor and then withdrawing treatment to allow VEGF levels to rebound in mice harboring mouse melanoma cells expressing VEGF165 allows tumor-associated endothelial cells transiently to support viral replication. This approach led to direct tumor cell lysis and triggered innate immune-mediated attack on the tumor vasculature. It also resulted in long-term antitumor effects, even against tumors in which viral replication is poorly supported. Since this combinatorial approach targets the tumor endothelium, we believe these data have direct, wide-ranging, and immediate clinical applicability across a broad range of tumor types.

Pharmacologic and Chemical Adjuvants in Tumor Virotherapy

For almost two decades, there has been interest in using viruses to deliver genes into cells. One particular approach consists of oncolytic viruses (OVs), which can selectively enter and replicate in neoplastic cells leading to their lytic destruction with minimal damage to surrounding normal tissue. OVs include a wide range of viruses that have been selected or genetically engineered such that viral replication is limited to permissive cancer cells with specific mutated cellular pathways. OVs have been designed to replicate only in tumors that have either activation of specific oncogenes or inactivation of specific tumor suppressor pathways.1–7 Table 1 presents an overview of specific OVs along with their salient properties that are being studied for the treatment of malignant gliomas. Table 1 Features of Oncolytic Viruses Being Used for Glioma Therapy Some OVs demonstrate selective tropism for entry into tumor cells.8–12 Second generation viruses that are “armed” by incorporation of prodrug activating genes,13–20 imaging genes,21,22 immunostimulatory genes,23–27 and antiangiogenesis genes28,29 are currently being investigated for safety and efficacy. The appropriate route of delivery of OVs remains to be defined in terms of advantages and disadvantages. For example, intratumoral viral delivery has the advantage of circumventing rapid viral clearance within the bloodstream due to antibody and complement neutralization of the virus, clearance by the liver, viral binding to nontumor cells that contain receptors for the virus, and barriers to migration across the vascular endothelium. However, intravenous administration is the route of choice for the treatment of both primary tumors that are not locally confined and metastatic disease. Methods of avoiding these limitations to viral administration will be discussed later in this review and include the development of various stealth agents and carrier cells to achieve nonimmunogenic viral delivery. With China's recent approval of the first oncolytic virus, adenovirus H101,30 a number of clinical trials are underway in the United States and Europe. Table 2 presents a summary of the glioma clinical trials that have been performed to date.31–38 Through the process of testing OVs in the clinic, however, a number of questions must be addressed. For instance, the pharmacokinetics of viral infection, replication, and spread should be ascertained noninvasively. Two novel oncolytic measles viruses are attempting to answer these questions. First, a measles virus encoding the soluble extracellular human carcinoembryonic antigen (CEA) allows for noninvasive analysis of viral propagation by measuring CEA levels.39,40 Second, by incorporating the thyroidal sodium iodide symporter in the measles vector, clinicians are able to use radioactive iodine tracers in order to monitor the status of viral infection using single-photon-emission computed tomography or positron-emission tomography.21,41–43 Beyond questions related to pharmacokinetics, clinical implementation of OVs is hampered by technical challenges in producing large amounts of high-titer virus. Lastly, performance of phase III clinical trials to assess clinical utility and guide the future directions of basic research in the field of OV therapy is needed. Table 2 Clinical Trials Using Oncolytic Viruses for the Treatment of Malignant Gliomasa For instance, preclinical data suggests that the ability of OVs to amplify within cancer cells should lead to increased intratumoral titers independent of the initial inoculum.1,27,44–48 While these findings have been corroborated by numerous in vitro findings, clinical efficacy has been limited due to significantly attenuated in vivo viral replication.49–56 In fact, a recent clinical trial shows replication of inoculated virus in tumor, albeit at levels that appear to be fairly reduced.32,57 Attenuated in vivo viral replication may be due to inefficient intratumoral viral dispersal, to barriers imposed by the tumor microenvironment, or to rapid viral clearance by host immune responses. Future clinical trials will need to take these host factors into account in order to achieve maximal OV-mediated tumoricidal activity while simultaneously avoiding systemic toxicity to the host. Elucidation of a variety of tumor- and host-based factors that limit viral infection, replication, and propagation could lead to the design of combinatorial molecular approaches combining oncolysis with pharmacologic agents designed to circumvent such host barriers to OV lysis of tumors. Additionally, certain classes of pharmacological agents can alter cellular homeostasis and activate cellular cascades that provide an environment conducive for viral replication. In this review, we will briefly describe both the current state of knowledge of host responses that limit OV therapy and the cellular pathways that can be targeted to enhance OV efficacy, followed by a review of potential pharmacologic and chemical approaches that could be employed to circumvent these obstacles.

784. Cell Carrier-Mediated Protection Allows for Systemic Delivery of Oncolytic Viruses in Virus-Immune Hosts

784. Cell Carrier-Mediated Protection Allows for Systemic Delivery of Oncolytic Viruses in Virus-Immune Hosts

404. Targeting the Tumor Vasculature To Enhance Systemic Delivery of Oncolytic Viruses

404. Targeting the Tumor Vasculature To Enhance Systemic Delivery of Oncolytic Viruses

Treg Depletion–enhanced IL-2 Treatment Facilitates Therapy of Established Tumors Using Systemically Delivered Oncolytic Virus

There are several roadblocks that hinder systemic delivery of oncolytic viruses to the sites of metastatic disease. These include the tumor vasculature, which provides a physical barrier to tumor-specific virus extravasation. Although interleukin-2 (IL-2) has been used in antitumor therapy, it is associated with endothelial cell injury, leading to vascular leak syndrome (VLS). Here, we demonstrate that IL-2-mediated VLS, accentuated by depletion of regulatory T cells (Treg), facilitates localization of intravenously (IV) delivered oncolytic virus into established tumors in immune-competent mice. IL-2, in association with Treg depletion, generates "hyperactivated" natural killer (NK) cells, possessing antitumor activity and secreting factors that facilitate virus spread/replication throughout the tumor by disrupting the tumor architecture. As a result, the combination of Treg depletion/IL-2 and systemic oncolytic virotherapy was found to be significantly more therapeutic against established disease than either treatment alone. These data demonstrate that it is possible to combine biological therapy with oncolytic virotherapy to generate systemic therapy against established tumors.

A smart move against cancer for vaccinia virus

Viruses can be more effective and less toxic than conventional drugs at killing cancer cells. Their complex interactions with cells allows virotherapists to design mutants to target pathways that are typically absent in tumour cells. Because viruses multiply themselves, lower concentrations than conventional drugs might be effective. Viruses from many different families are being proposed for oncolytic development. 1 Guo ZS Thorne SH Bartlett DL Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses. Biochim Biophys Acta. 2008; 1785: 217-231 PubMed Google Scholar Of them, vaccinia virus has unique properties to fight cancer: fast replication, haematogenous spread, a good safety record as a vaccine against smallpox, and genomic space to insert transgenes. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trialIntratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. Full-Text PDF

Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy

Live cells offer unique advantages as vehicles for systemic oncolytic virus (OV) delivery. Recent studies from our laboratory and others have shown that virus-infected cells can serve as Trojan horse vehicles to evade antiviral mechanisms encountered in the bloodstream, prevent uptake by off-target tissues and act as microscale factories to produce OV upon arrival in tumor beds. However to be employed effectively, OV-infected cells are best viewed as dynamic biological systems rather than static therapeutic agents. The time-dependent processes of infection and in vivo cell trafficking will inevitably vary depending on which particular OV is being delivered, as well as the type of carrier cells (CC) employed. Understanding these parameters with respect to each unique CC/OV combination will therefore be required in order to effectively evaluate and harness their potential in preclinical study. In the following review, we discuss how early studies of OV delivery led us to investigate the use of cell carriers in our laboratory, and the approaches we are currently undertaking to compare the dynamics of different CC/OV systems. On the basis of these studies and others it is apparent that the success of any cell-based system for OV delivery rests upon the coordinated timing of three sequential phases--(1) ex vivo loading, (2) stealth delivery and (3) virus production at the tumor site. While at the current time, the timing of these processes are coupled to the natural cycle of infection and in vivo trafficking properties innate to each cell virus system, a quantitative delineation of their dynamics will lay the foundation for engineering CC/OV biotherapeutic systems that can be clinically deployed in a highly directed and controlled manner.