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We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth.
Mol Ther 2008 Oct
PMID:Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model. 1866 55

Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine, whereas nerve growth factor (NGF) is a neurotrophin that can promote neural cell survival, differentiation and maturation. However, recent papers indicate that TNF-alpha has a pivotal role in fate decisions of neural cells in normal noninflammatory conditions, whereas NGF contributes to maintenance of inflammation. Although these observations suggest a close relationship between NGF and TNF-alpha signalling, crosstalk between these factors is not fully understood. In this Opinion article, we review recent reports regarding possible crosstalk between NGF and TNF-alpha and we propose a positive-feedback loop of their expression. We discuss the possible mechanisms by which disturbance of the crosstalk could contribute to diseases such as cancer and Alzheimer's disease.
Trends Mol Med 2008 Sep
PMID:Interpreting crosstalk between TNF-alpha and NGF: potential implications for disease. 1869 38

Many viruses, either naturally occurring or as a result of genetic manipulation, exhibit conditional replication in transformed cells. This principle is the basis for experimental therapeutic approaches exploiting the oncolytic potential of such agents without the danger of collateral damage to resistant normal tissues. One of the potential obstacles to these approaches is the possibility of genetic adaptation of oncolytic viruses upon replication in susceptible tumor tissues. Genetic variation can reverse genetic manipulations of parental viral genomes that determine attenuation of virulence, selective tumor cell tropism or other desirable traits. Alternatively, it may convey new properties not originally associated with parental strains, e.g., adaptation to a human host range. We examined genetic stability of an oncolytic nonpathogenic poliovirus recombinant considered for therapy of recurrent glioblastoma multiforme (GBM). This was done by serial passage experiments in glioma xenografts in vivo and investigation of phenotypic and genotypic markers of attenuation. Intratumoral inoculation of oncolytic poliovirus produced efficient tumor regress and elimination without altering temperature-sensitive growth, selective cytotoxicity, or genetic markers of attenuation of virus recovered from inoculated animals. Our studies demonstrate that active viral oncolysis of malignant glioma does not alter the conditional replication properties of oncolytic nonpathogenic poliovirus recombinants.
Mol Ther 2008 Nov
PMID:Recombinant oncolytic poliovirus eliminates glioma in vivo without genetic adaptation to a pathogenic phenotype. 1876 73

To protect viral particles from neutralization, sequestration, nonspecific adhesion, and mislocalization following systemic delivery, we have previously exploited the natural tumor-homing properties of antigen-specific CD8+ T cells. Thus, OT-I T cells, preloaded in vitro with the oncolytic vesicular stomatitis virus (VSV), can deliver virus to established B16ova tumors to generate significantly better therapy than that achievable with OT-I T cells, or systemically delivered VSV, alone. Here, we demonstrate that preconditioning immune-competent mice with Treg depletion and interleukin-2 (IL-2), before adoptive T-cell therapy with OT-I T cells loaded with VSV, leads to further highly significant increases in antitumor therapy. Therapy was associated with antitumor immune memory, but with no detectable toxicities associated with IL-2, Treg depletion, or systemic dissemination of the oncolytic virus. Efficacy was contributed by multiple factors, including improved persistence of T cells; enhanced delivery of VSV to tumors; increased persistence of OT-I cells in vivo resulting from tumor oncolysis; and activation of NK cells, which acquire potent antitumor and proviral activities. By controlling the levels of virus loaded onto the OT-I cells, adoptive therapy was still effective in mice preimmune to the virus, indicating that therapy with virus-loaded T cells may be useful even in virus-immune patients. Taken together, our data show that it is possible to combine adoptive T-cell therapy, with biological therapy (Treg depletion+IL-2), and VSV virotherapy, to treat established tumors under conditions where none of the individual modalities alone is successful.
Mol Ther 2008 Dec
PMID:Use of biological therapy to enhance both virotherapy and adoptive T-cell therapy for cancer. 1882 7

Primary and metastatic neoplasms of the liver account for more than a million deaths per year worldwide. Despite decades of research, effective novel therapies for these cancers are urgently needed. Oncolytic virotherapeutics represent a novel class of pharmacophore that holds promise for the treatment of hepatic neoplasms. Cancer-specific replication is followed by oncolysis, virus spreading and infection of adjacent cancer cells. This process is then repeated. Virotherapeutics target multiple genetic pathways involved in carcino-genesis, and demonstrate activity against apoptosis-resistant tumour cells. This platform can also exploit the advantage of multiple intrinsic anti-cancer therapeutic mechanisms, combining direct viral oncolysis with therapeutic transgene expression. Recent advances in pre-clinical and clinical studies are revealing the potential of this unique therapeutic class, in particular for liver cancers. This review summarizes the available data on applying oncolytic virotherapeutics to hepatic neoplasms to date, and discusses the challenges and future directions for virotherapy.
J Cell Mol Med 2009 Jul
PMID:Oncolytic virotherapy for advanced liver tumours. 1917 89

Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Hence, novel cancer therapies will need to be tested for both tumor regression and CSC targeting. Herein we show that oncolytic reovirus that induces regression of human breast cancer primary tumor samples xenografted in immunocompromised mice also effectively targets and kills CSCs in these tumors. CSCs were identified based on CD24(-)CD44(+) cell surface expression and overexpression of aldehyde dehydrogenase. Upon reovirus treatment, the CSC population was reduced at the same rate as non-CSCs within the tumor. Immunofluorescence of breast tumor tissue samples from the reovirus- and mock-treated mice confirmed that both CSCs and non-CSCs were infectible by reovirus, and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay showed that both populations died by apoptosis. Ras, which has been shown to mediate reovirus oncolysis, was found to be present at similar levels in all cell types, and this is consistent with their comparable sensitivity to reovirus. These experiments indicate that oncolytic reovirus has the potential to induce tumor regression in breast cancer patients. More important, the CSC population was equally reduced and was as susceptible to reovirus treatment as the non-CSC population.
Mol Ther 2009 Jun
PMID:Oncolytic reovirus effectively targets breast cancer stem cells. 1929 72

Colorectal carcinoma (CRC) constitutes a common malignancy with limited therapeutic options in metastasized stages. Mesenchymal stem cells (MSC) home to tumours and may therefore serve as a novel therapeutic tool for intratumoral delivery of antineoplastic factors. Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) which promises apoptosis induction preferentially in tumour cells represents such a factor. We generated TRAIL-MSC by transduction of human MSC with a third generation lentiviral vector system and analysed their characteristics and capacity to inhibit CRC growth. (1) TRAIL-MSC showed stable transgene expression with neither changes in the defining MSC characteristics nor signs of malignant transformation. (2) Upon direct in vitro coculture TRAIL-MSC induced apoptosis in TRAIL-sensitive CRC-cell lines (DLD-1 and HCT-15) but also in CRC-cell lines resistant to soluble TRAIL (HCT-8 and SW480). (3) In mixed subcutaneous (s.c.) xenografts TRAIL-MSC inhibited CRC-tumour growth presumably by apoptosis induction but a substantial proportion of TRAIL-MSC within the total tumour cell number was needed to yield such anti-tumour effect. (4) Systemic application of TRAIL-MSC had no effect on the growth of s.c. DLD-1 xenografts which appeared to be due to a pulmonary entrapment and low rate of tumour integration of TRAIL-MSC. Systemic TRAIL-MSC caused no toxicity in this model. (5) Wild-type MSC seemed to exert a tumour growth-supporting effect in mixed s.c. DLD-1 xenografts. These novel results support the idea that lentiviral TRAIL-transgenic human MSC may serve as vehicles for clinical tumour therapy but also highlight the need for further investigations to improve tumour integration of transgenic MSC and to clarify a potential tumour-supporting effect by MSC.
J Cell Mol Med 2010 Sep
PMID:Growth inhibition of colorectal carcinoma by lentiviral TRAIL-transgenic human mesenchymal stem cells requires their substantial intratumoral presence. 1950 88

Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity. Because the malignant phenotype of tumours is the culmination of multiple mutations that occur in several genes eventually leading to aberrant signalling pathways, oncolytic viruses, either natural or engineered, specifically target tumour cells, taking advantage of this cellular deviant signalling for their replication. Reovirus is one such naturally occurring double-stranded RNA (dsRNA) virus that exploits altered Ras signalling pathways in a myriad of cancers. The ability of reovirus to infect and lyse tumours both solid and haematological, under in vitro, in vivo, and ex vivo conditions, is discussed in this chapter. The major mechanism of reovirus oncolysis of cancer cells has been shown to occur through apoptosis. In addition, the synergistic anti-tumour effects of reovirus in combination with radiation or chemotherapy has also been demonstrated for reovirus-resistant and moderately sensitive tumours. In most of the clinical trials undertaken to date, an anti-reovirus immune response has been seen likely circumventing efficacy. Investigation into the use of reovirus as an immune adjuvant is currently underway to try and re-direct this immune response to tumour. Reovirus phase I clinical trials have shown indications of efficacy and several phase I/II trials are ongoing at present. The extensive pre-clinical efficacy, replication competency, and low toxicity profile in humans has placed the reovirus as an attractive anti-cancer therapeutic for ongoing clinical testing.
Methods Mol Biol 2009
PMID:Oncolytic viral therapy using reovirus. 1956 24

This review deals with the avian paramyxovirus Newcastle disease virus (NDV) and describes properties that explain its oncolytic activity, its tumor-selective replication behavior, and its immune-stimulatory capacity with human cells. The strong interferon response of normal cells upon contact with NDV appears to be the basis for the good tolerability of the virus in cancer patients and for its immune stimulatory properties, whereas the weak interferon response of tumor cells explains the tumor selectivity of replication and oncolysis. Various concepts for the use of this virus for cancer treatment are pointed out and results from clinical studies are summarized. Reverse genetics technology has made it possible recently to clone the genome and to introduce new foreign genes thus generating new recombinant viruses. These can, in the future, be used to transfer new therapeutic genes into tumors and also to immunize against new emerging pathogens. The modular nature of gene transcription, the undetectable rate of recombination, and the lack of a DNA phase in the replication cycle make NDV a suitable candidate for the rational design of a safe and stable vaccine and gene therapy vector.
Methods Mol Biol 2009
PMID:Newcastle disease virus: a promising vector for viral therapy, immune therapy, and gene therapy of cancer. 1956 23

As a new anticancer treatment option, vaccinia virus (VACV) has shown remarkable antitumor activities (oncolysis) in preclinical studies, but potential infection of other organs remains a safety concern. We present here genome comparisons between the de novo sequence of GLV-1h68, a recombinant VACV, and other VACVs. The identified differences in open reading frames (ORFs) include genes encoding host-range selection, virulence and immune modulation proteins, e.g., ankyrin-like proteins, serine proteinase inhibitor SPI-2/CrmA, tumor necrosis factor (TNF) receptor homolog CrmC, semaphorin-like and interleukin-1 receptor homolog proteins. Phylogenetic analyses indicate that GLV-1h68 is closest to Lister strains but has lost several ORFs present in its parental LIVP strain, including genes encoding CrmE and a viral Golgi anti-apoptotic protein, v-GAAP. The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma. The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L-null and revertant viruses. GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism.
Mol Genet Genomics 2009 Oct
PMID:The highly attenuated oncolytic recombinant vaccinia virus GLV-1h68: comparative genomic features and the contribution of F14.5L inactivation. 1970 52


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