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.