Cytokine & Growth Factor Reviews RSS feed: Current Issue. Cytokine & Growth Factor Reviews publishes thought-provoking articles (critical reviews, state-of-the-art reviews, letters to the editor, meeting reviews) devoted to important advances in the rapidly changing fields of growth factor and cytokine research. Major emphasis is placed on the multidisciplinary significance of cytokines and growth factors in areas as diverse as signal transduction, cell growth and differentiation, embryonic development, immunology, tumorigenesis and clinical medicine.http://www.cgfr.co.uk/?rss=yesElsevier Inc.en © 2010 Published by Elsevier Inc. All rights reserved. Cytokine & Growth Factor Reviews1359-6101212-3April 2010 © 2010 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.cgfr.co.uk/article/PIIS1359610110000389/abstract?rss=yesEditorial Board10.1016/S1359-6101(10)00038-9Cytokine & Growth Factor Reviews 21, 2 (2010)2010-04-01Cytokine & Growth Factor Reviews2010-04-01212-3S1359-6101(10)X0003-XCO2CO2http://www.cgfr.co.uk/article/PIIS135961011000033X/abstract?rss=yesThe First International Oncolytic Virus Meeting was organized by Stephen Russell and colleagues at the Mayo Clinic in Rochester, Minnesota in the fall of 2001. Those of us who attended this initial meeting recognized that there was a small but critical mass of scientists around the world who saw the promise of replicating viruses as cancer therapeutics, but at the same time realized that we needed to band together if this field was to move from laboratory curiosity to clinical implementation. Indeed, the first meeting was “all you wanted to know about oncolytic adenovirus”, with very little discussion of alternate virus platforms and a real paucity of clinical data.ForewordJohn Bell, David Kirn10.1016/j.cytogfr.2010.04.004Cytokine & Growth Factor Reviews 21, 2 (2010)2010-05-05Cytokine & Growth Factor Reviews2010-05-05212-3S1359-6101(10)X0003-X8384http://www.cgfr.co.uk/article/PIIS1359610110000122/abstract?rss=yesAbstract: Chemotherapy remains a common mode of anticancer treatment even though in most cancer indications the therapeutic approach is not effective and ultimately associated with the onset of chemoresistance. A better understanding of genetic differences in tumors ushered in the era of targeted therapy which has revolutionized the treatment of certain cancer types. However, generally targeted therapies are only cytostatic and a proportion of the patient population may be non-responsive to targeted therapy due to mutations of other genes in the same pathway (e.g. ras mutations in patients with colorectal cancer treated with EGFR targeted therapy). Therefore, there exists a need for a radically new approach to cancer therapy. Oncolytic viruses (OVs) possess many properties of an ideal cancer therapeutic. OVs are cytotoxic and target cancers via multiple mechanisms of action while at the same time exploiting validated genetic pathways known to be dysregulated in many cancers. Indeed, promising safety and efficacy data has emerged from Phase 1 and Phase 2 trials with diverse OVs (e.g. JX-594, a targeted oncolytic poxvirus). Though the field has lagged behind with pivotal, randomized Phase 3 trials, these are currently being initiated for a number of OVs. In addition, the field must ensure a continued clinical development of newly developed OVs; a strategy for the clinical development of novel cancer therapeutics is outlined.Navigating the clinical development landscape for oncolytic viruses and other cancer therapeutics: No shortcuts on the road to approvalCaroline J. Breitbach, Tony Reid, James Burke, John C. Bell, David H. Kirn10.1016/j.cytogfr.2010.02.001Cytokine & Growth Factor Reviews 21, 2 (2010)2010-05-18Cytokine & Growth Factor Reviews2010-05-18212-3S1359-6101(10)X0003-X8589http://www.cgfr.co.uk/article/PIIS1359610110000171/abstract?rss=yesAbstract: It is time for those working on oncolytic viruses to take stock of the status of the field. We now have at our disposal an array of potential therapeutic agents, and are beginning to conduct early-phase clinical trials in patients with relapsed/metastatic cancers. By drawing on lessons learned during the development of other biological therapies, such as monoclonal antibodies and targeted small molecule inhibitors, we are now in a position to chart the course of the next wave of trials that will go beyond the phase I studies of safety and feasibility. In this article we review our approach to the development of oncolytic viruses as cancer therapeutics. In doing so, we emphasise the fact that this process is modular and involves multiple iterative steps between the laboratory and the clinic. Ultimately, at least in the medium term, the future of oncolytic virotherapy lies in combination regimens with standard anti-cancer agents such as radiation and chemotherapy.Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeuticsK.J. Harrington, R.G. Vile, A. Melcher, J. Chester, H.S. Pandha10.1016/j.cytogfr.2010.02.006Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-11Cytokine & Growth Factor Reviews2010-03-11212-3S1359-6101(10)X0003-X9198http://www.cgfr.co.uk/article/PIIS1359610110000146/abstract?rss=yesAbstract: Approximately 50,000 cases of superficial bladder cancer are diagnosed annually in the United States. Immunotherapy utilizing intravesical BCG is the most effective standard therapy for superficial transitional cell carcinoma of the bladder. Based on ease of administration, limited systemic dissemination, and the demonstrated activity of immunotherapy, superficial bladder cancer is an excellent target for virus based gene and immunotherapy. Thus far, clinical trials of virus therapy for bladder cancer have yielded mixed results. In this paper the results of several virus based clinical trials for bladder cancer are reviewed.Virus therapy for bladder cancerJames Burke10.1016/j.cytogfr.2010.02.003Cytokine & Growth Factor Reviews 21, 2 (2010)2010-04-12Cytokine & Growth Factor Reviews2010-04-12212-3S1359-6101(10)X0003-X99102http://www.cgfr.co.uk/article/PIIS1359610110000304/abstract?rss=yesAbstract: The concept of oncolytic viral therapy has a century-old history, but only within the last 20 years have oncolytic viruses been considered for the treatment of brain cancers. Viruses such as herpes, measles, and vaccinia have all been known to cause devastating cases of neurological disease in humans, yet these ‘scourges’ are now being harnessed in such a way that they prove very useful as cancer therapeutics. There have been 8 formal clinical trials and 3 case studies using oncolytic viruses to treat malignant glioma patients. Although some success has been reached with oncolytic therapy, overall it has fallen short of expectations. In this review we analyze the results of these trials and bring to light some of the limitations and pitfalls of this therapy, as well as present some promising preclinical work that has been proposed to circumvent such problems.Oncolytic viruses as experimental treatments for malignant gliomas: Using a scourge to treat a devilFranz J. Zemp, Juan Carlos Corredor, Xueqing Lun, Daniel A. Muruve, Peter A. Forsyth10.1016/j.cytogfr.2010.04.001Cytokine & Growth Factor Reviews 21, 2 (2010)2010-05-19Cytokine & Growth Factor Reviews2010-05-19212-3S1359-6101(10)X0003-X103117http://www.cgfr.co.uk/article/PIIS1359610110000158/abstract?rss=yesAbstract: The systemic administration of oncolytic virus (OV) is often inefficient due to clearance of the virus by host defense mechanism and spurious targeting of non-cancer tissues through the bloodstream. Cell mediated OV delivery could hide the virus from host defenses and direct them toward tumors: Mesencymal and neural stem cells have been described to possess tumor-homing ability as well as the capacity to deliver OVs. In this review, we will focus on approaches where OV and carrier cells are utilized for cancer therapy. Effective cellular internalization and replication of OVs need to occur both in cancer and carrier cells. We thus will discuss the current challenges faced by the use of OV delivery via carrier cells.Directing systemic oncolytic viral delivery to tumors via carrier cellsHiroshi Nakashima, Balveen Kaur, E.A. Chiocca10.1016/j.cytogfr.2010.02.004Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-12Cytokine & Growth Factor Reviews2010-03-12212-3S1359-6101(10)X0003-X119126http://www.cgfr.co.uk/article/PIIS1359610110000250/abstract?rss=yesAbstract: Interactions between tumor cells and their microenvironment have been shown to play a very significant role in the initiation, progression, and invasiveness of cancer. These tumor–stromal interactions are capable of altering the delivery and effectiveness of therapeutics into the tumor and are also known to influence future resistance and re-growth after treatment. Here we review recent advances in the understanding of the tumor microenvironment and its response to oncolytic viral therapy. The multifaceted environmental response to viral therapy can influence viral infection, replication, and propagation within the tumor. Recent studies have unveiled the complicated temporal changes in the tumor vasculature post-oncolytic virus (OV) treatment, and their impact on tumor biology. Similarly, the secreted extracellular matrix in solid tumors can affect both infection and spread of the therapeutic virus. Together, these complex changes in the tumor microenvironment also modulate the activation of the innate antiviral host immune response, leading to quick and efficient viral clearance. In order to combat these detrimental responses, viruses have been combined with pharmacological adjuvants and “armed” with therapeutic genes in order to suppress the pernicious environmental conditions following therapy. In this review we will discuss the impact of the tumor environment on viral therapy and examine some of the recent literature investigating methods of modulating this environment to enhance oncolysis.Impact of tumor microenvironment on oncolytic viral therapyJeffrey Wojton, Balveen Kaur10.1016/j.cytogfr.2010.02.014Cytokine & Growth Factor Reviews 21, 2 (2010)2010-04-20Cytokine & Growth Factor Reviews2010-04-20212-3S1359-6101(10)X0003-X127134http://www.cgfr.co.uk/article/PIIS1359610110000183/abstract?rss=yesAbstract: Oncolytic viruses (OVs) are selected based on their ability to eliminate malignancies by direct infection and lysis of cancer cells. Originally, OVs were designed to target malignancies by taking advantage of the defects of cancer cells observed in vitro. Subsequent analysis of virus delivery and spread in vivo has demonstrated that the tumour microenvironment can impede the ability of OVs to effectively infect and spread. Despite this limitation, it is becoming increasingly evident that OVs are also able to take advantage of certain features of the tumour microenvironment. Currently, a growing body of the literature is delineating the complex interaction between OVs and the tumour microenvironment that results in an additional therapeutic activity; these viruses are able to target malignancies by rapidly altering the tumour microenvironment into a milieu that potentiates anticancer activity. Herein, we discuss strategies that capitalize on the multifaceted relationship between OVs and host–tumour interactions that enhance the toxicity of OVs to the tumour microenvironment.Double trouble for tumours: Exploiting the tumour microenvironment to enhance anticancer effect of oncolytic virusesNaomi De Silva, Harold Atkins, David H. Kirn, John C. Bell, Caroline J. Breitbach10.1016/j.cytogfr.2010.02.007Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-26Cytokine & Growth Factor Reviews2010-03-26212-3S1359-6101(10)X0003-X135141http://www.cgfr.co.uk/article/PIIS1359610110000201/abstract?rss=yesAbstract: The interactions between the immune system, a malignant tumour and an oncolytic virus are complex and poorly understood. For oncolytic viruses to become successful therapeutics we need to better understand these interactions and identify strategies to take advantage of defects in the innate immune response within tumours and avoid cellular anti-viral responses while capitalizing on anti-tumoural immunity. In this review we will discuss the evidence for the induction of tumour-specific immune responses by oncolytic viruses as well as by cancer vaccines. We will then describe some of the barriers to successful cancer immunotherapy, and finally we will outline a strategy for enhancing anti-tumoural immunity while reducing anti-viral immunity by combining tumour vaccination with oncolytic viral therapy.Combining oncolytic virotherapy and tumour vaccinationByram W. Bridle, Stephen Hanson, Brian D. Lichty10.1016/j.cytogfr.2010.02.009Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-12Cytokine & Growth Factor Reviews2010-03-12212-3S1359-6101(10)X0003-X143148http://www.cgfr.co.uk/article/PIIS1359610110000134/abstract?rss=yesAbstract: Monoclonal antibody therapy for cancer has significantly altered the natural history of several common cancers. This success was attained only after many years of failure to understand the technical limitations of antibody therapy. In order to further exploit the immune system, tumor vaccine strategies are an active research focus. Virus based immune agents including GM-CSF armed vectors are among these early efforts. Herpes, adenovirus, and vaccinia based vectors encoding GM-CSF have reported intriguing early clinical trial results that are reviewed here.GM-CSF-armed, replication-competent viruses for cancerJames M. Burke10.1016/j.cytogfr.2010.02.002Cytokine & Growth Factor Reviews 21, 2 (2010)2010-04-09Cytokine & Growth Factor Reviews2010-04-09212-3S1359-6101(10)X0003-X149151http://www.cgfr.co.uk/article/PIIS1359610110000274/abstract?rss=yesAbstract: Oncolytic viruses (OVs) have shown promise as cancer therapeutics in pre-clinical and clinical testing; however, it is unlikely that OVs will constitute a stand-alone treatment. Histone deacetylase inhibitors (HDIs) represent a class of anticancer agents known to influence epigenetic modifications of chromatin, alter gene expression and manipulate a variety of signaling pathways, in some cases blunting the cellular antiviral response. Recent studies have shown that combining OV therapy with HDI treatment enhances viral replication and synergistically induces the killing of cancer cells in vitro and in vivo, an effect that has now been demonstrated in variety of virus/HDI combinations. This review discusses the results obtained with the different OV/HDI combinations, the rationale supporting these combinations and the advantages for oncolytic virus therapy.Oncolytic viruses and histone deacetylase inhibitors—A multi-pronged strategy to target tumor cellsThi Lien-Anh Nguyen, Marnie Goodwin Wilson, John Hiscott10.1016/j.cytogfr.2010.03.002Cytokine & Growth Factor Reviews 21, 2 (2010)2010-04-15Cytokine & Growth Factor Reviews2010-04-15212-3S1359-6101(10)X0003-X153159http://www.cgfr.co.uk/article/PIIS1359610110000249/abstract?rss=yesAbstract: Replicating virus-based therapeutics for cancer, or oncolytic virus therapy (OVT), is rapidly emerging as a promising treatment modality for a wide range of cancers. In pre-clinical studies, oncolytic viruses have produced remarkable results in a variety of experimental animal models, and several viruses have entered phase I/II clinical trials. However, OVT is not effective against all tumours, with major treatment bottlenecks being the inability to infect, replicate within, or kill certain cancer cells. Unfortunately, the underlying molecular mechanisms governing these limitations are largely unknown. Recently, RNAi technology has been adapted for systematic interrogation of entire eukaryotic genomes. Since then, several groups have conducted genome-wide RNAi screens to study host/virus interactions. Herein we briefly summarize RNAi screening and its recent application to virology, and propose its use in overcoming key barriers to successful OVT.A call to arms: Using RNAi screening to improve oncolytic viral therapyD.J. Mahoney, D.F. Stojdl10.1016/j.cytogfr.2010.02.013Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-08Cytokine & Growth Factor Reviews2010-03-08212-3S1359-6101(10)X0003-X161167http://www.cgfr.co.uk/article/PIIS1359610110000213/abstract?rss=yesAbstract: High-dose chemotherapy and radiation followed by autologous blood and marrow transplantation (ABMT) has been used for the treatment of certain cancers that are refractory to standard therapeutic regimes. However, a major challenge with ABMT for patients with hematologic malignancies is disease relapse, mainly due to either contamination with cancerous hematopoietic stem and progenitor cells (HSPCs) within the autograft or the persistence of residual therapy-resistant disease niches within the patient. Oncolytic viruses represent a promising therapeutic approach to prevent cancer relapse by eliminating tumor-initiating cells that contaminate the autograft. Here we summarize an ex vivo “purging” strategy with oncolytic Myxoma virus (MYXV) to remove cancer-initiating cells from patient autografts prior to transplantation. MYXV, a novel oncolytic poxvirus with potent anti-cancer properties in a variety of in vivo tumor models, can specifically eliminate cancerous stem and progenitor cells from samples obtained from acute myelogenous leukemia (AML) patients, while sparing normal CD34+ hematopoietic stem and progenitor cells capable of rescuing hematopoiesis following high dose conditioning. We propose that a broader subset of patients with intractable hematologic malignancies who have failed standard therapy could become eligible for ABMT when the treatment schema is coupled with ex vivo oncolytic therapy.Oncolytic viral purging of leukemic hematopoietic stem and progenitor cells with Myxoma virusMasmudur M. Rahman, Gerard J. Madlambayan, Christopher R. Cogle, Grant McFadden10.1016/j.cytogfr.2010.02.010Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-08Cytokine & Growth Factor Reviews2010-03-08212-3S1359-6101(10)X0003-X169175http://www.cgfr.co.uk/article/PIIS1359610110000237/abstract?rss=yesAbstract: The use of viruses as targeted cancer therapy has shown significant promise, and the list of oncolytic viruses continue to grow. The interest in unexplored viruses as oncolytic agents is a natural corollary to the successes and challenges of those already being examined in the clinical setting. Are these ‘new’ viruses any more effective than their predecessors? What are the benefits of refining current clinical candidates compared to searching for new ones? This review briefly describes some of these novel oncolytic viruses. It also examines the issues that arise in comparing them to each other. We believe that the viral mechanism of action is a key factor to success and suggest guidelines by which all oncolytic virus candidates could be evaluated.Novel oncolytic viruses: Riding high on the next wave?Marianne M. Stanford, John C. Bell, Markus J.V. Vähä-Koskela10.1016/j.cytogfr.2010.02.012Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-11Cytokine & Growth Factor Reviews2010-03-11212-3S1359-6101(10)X0003-X177183http://www.cgfr.co.uk/article/PIIS1359610110000225/abstract?rss=yesAbstract: The experimental infectivity and excellent tolerance of some rodent autonomous parvoviruses in humans, together with their oncosuppressive effects in preclinical models, speak for the inclusion of these agents in the arsenal of oncolytic viruses under consideration for cancer therapy. In particular, wild-type parvovirus H-1PV can achieve a complete cure of various tumors in animal models and kill tumor cells that resist conventional anticancer treatments. There is growing evidence that H-1PV oncosuppression involves an immune component in addition to the direct viral oncolytic effect. This article summarizes the recent assessment of H-1PV antineoplastic activity in glioma, pancreatic ductal adenocarcinoma, and non-Hodgkin lymphoma models, laying the foundation for the present launch of a first phase I/IIa clinical trial on glioma patients.Oncolytic parvoviruses as cancer therapeuticsJean Rommelaere, Karsten Geletneky, Assia L. Angelova, Laurent Daeffler, Christiane Dinsart, Irina Kiprianova, Joerg R. Schlehofer, Zahari Raykov10.1016/j.cytogfr.2010.02.011Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-08Cytokine & Growth Factor Reviews2010-03-08212-3S1359-6101(10)X0003-X185195http://www.cgfr.co.uk/article/PIIS135961011000016X/abstract?rss=yesAbstract: PVS-RIPO is a genetically recombinant, non-pathogenic poliovirus chimera with a tumor-specific conditional replication phenotype. Consisting of the genome of the live attenuated poliovirus type 1 (Sabin) vaccine with its cognate IRES element replaced with that of human rhinovirus type 2, PVS-RIPO displays an inability to translate its genome in untransformed neuronal cells, but effectively does so in cells originating from primary tumors in the central nervous system or other cancers. Hence, PVS-RIPO unleashes potent cytotoxic effects on infected cancer cells and produces sustained anti-tumoral responses in animal tumor models. PVS-RIPO presents a novel approach to the treatment of patients with glioblastoma multiforme, based on conditions favoring an unconventional viral translation initiation mechanism in cancerous cells. In this review we summarize advances in the understanding of major molecular determinants of PVS-RIPO oncolytic efficacy and safety and discuss their implications for upcoming clinical investigations.Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiformeChristian Goetz, Matthias Gromeier10.1016/j.cytogfr.2010.02.005Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-18Cytokine & Growth Factor Reviews2010-03-18212-3S1359-6101(10)X0003-X197203http://www.cgfr.co.uk/article/PIIS1359610110000195/abstract?rss=yesAbstract: There is an urgent need for innovative therapeutic strategies to treat aggressive metastatic cancers that are incurable with standard therapeutic approaches. Novel treatment strategies like oncolytic virotherapy have led, in some cases, to impressive effects on disease progression in human trials, suggesting that approval of an oncolytic virus therapeutic is on the horizon. While combinations of oncolytic viruses with small molecules are already being tested and have shown promise, we propose that even greater therapeutic synergies could be achieved through rational design of complementary virus therapeutics. In this review, we discuss rational chemical and biological combination strategies to enhance oncolytic virotherapy highlighting the promising combination of vaccinia and vesicular stomatitis oncolytic viruses.United virus: The oncolytic tag-team against cancer!Fabrice Le Bœuf, John C. Bell10.1016/j.cytogfr.2010.02.008Cytokine & Growth Factor Reviews 21, 2 (2010)2010-03-15Cytokine & Growth Factor Reviews2010-03-15212-3S1359-6101(10)X0003-X205211