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Viruses can be engineered or adapted for selective propagation in neoplastic tissues and further modified for therapeutic transgene expression to enhance their antitumor potency and druggability. Oncolytic viruses (OVs) can be administered locally or intravenously and spread to a variable degree at sites of tumor growth. OV-infected tumor cells die in situ, releasing viral and tumor antigens that are phagocytosed by macrophages, transported to regional lymph nodes, and presented to antigen-reactive T cells, which proliferate before dispersing to kill uninfected tumor cells at distant sites. Several OVs are showing clinical promise, and one of them, talimogene laherparepvec (T-VEC), was recently granted marketing approval for intratumoral therapy of nonresectable metastatic melanoma. T-VEC also appears to substantially enhance clinical responsiveness to checkpoint inhibitor antibody therapy. Here, we examine the T-VEC paradigm and review some of the approaches currently being pursued to develop the next generation of OVs for both local and systemic administration, as well as for use in combination with other immunomodulatory agents. Russell and Peng review the field of oncolytic virotherapy, highlighting the recent approval of intralesional talimogene laherparepvec (T-VEC) for metastatic melanoma and its synergistic interaction with checkpoint inhibitor antibodies. They then explore how newer OVs may further improve treatment outcomes in the post-T-VEC era.

Since the turn of the nineteenth century, when their existence was first recognized, viruses have attracted considerable interest as possible agents of tumor destruction. Early case reports emphasized regression of cancers during naturally acquired virus infections, providing the basis for clinical trials where body fluids containing human or animal viruses were used to transmit infections to cancer patients. Most often the viruses were arrested by the host immune system and failed to impact tumor growth, but sometimes, in immunosuppressed patients, infection persisted and tumors regressed, although morbidity as a result of the infection of normal tissues was unacceptable. With the advent of rodent models and new methods for virus propagation, there were numerous attempts through the 1950s and 1960s to force the evolution of viruses with greater tumor specificity, but success was limited and many researchers abandoned the field. Technology employing reverse genetics later brought about a renewal of interest in virotherapy that allowed the generation of more potent, tumor-specific oncolytics. Here, examination of early oncolytic virotherapy before genetic engineering serves to highlight tremendous advances, yet also hints at ways to penetrate host immune defenses, a significant remaining challenge in modern virotherapy research.

About the Authors: Roberto Cattaneo * E-mail: Cattaneo.Roberto@mayo.edu Affiliation: Department of Molecular Medicine and Virology and Gene Therapy Graduate School track, Mayo Clinic, Rochester, Minnesota, United States of America Stephen J. Russell Affiliation: Department of Molecular Medicine and Virology and Gene Therapy Graduate School track, Mayo Clinic, Rochester, Minnesota, United States of AmericaCitation: Cattaneo R, Russell SJ (2017) How to develop viruses into anticancer weapons. Competing interests: SJR is a scientific cofounder, equity stakeholder, board member and serves as CEO at Vyriad, a company that is developing oncolytic measles viruses for cancer therapy. In the mid-20th century, the principle of virus attenuation through adaptation to unnatural hosts was extended to cultured cells: cells from different species were used to select viruses with multiple mutations, reducing replication speed and allowing the immune system to control viral infection. [...]subunit vaccines are proving to be effective against virus-induced cancers, preventing hepatitis B virus-induced hepatocellular carcinoma and human papilloma virus-induced cervical cancer [2, 4]. Intentional transmission of virus infections was then pursued in a range of cancer types using several different virus isolates (most notably West Nile, mumps, and adenovirus) and led to definite tumor regressions but sometimes also to fatal encephalitis, as with West Nile virus in immunosuppressed lymphoma patients [8]. [...]the vaccine lineage-based measles virus (MeV) platform we have developed can enter many cell types through the ubiquitously expressed protein CD46, while future clinical trials may be based on viruses with targeted tropism. [...]targeted cell entry and cell-cell fusion: the two-protein MeV...

MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 1011 TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.

Multiple myeloma remains an incurable neoplasm of plasma cells that affects more than 20,000 people annually in the United States. There has been a veritable revolution in this disease during the past decade, with dramatic improvements in our understanding of its pathogenesis, the development of several novel agents, and a concomitant doubling in overall survival. Because multiple myeloma is a complex and wide-ranging disorder, its management must be guided by disease- and patient-related factors; emerging as one of the most influential factors is risk stratification, primarily based on cytogenetic features. A risk-adapted approach provides optimal therapy to patients, ensuring intense therapy for aggressive disease and minimizing toxic effects, providing sufficient but less intense therapy for low-risk disease. This consensus statement reflects recommendations from more than 20 Mayo Clinic myeloma physicians, providing a practical approach for newly diagnosed patients with myeloma who are not enrolled in a clinical trial.

Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5′-noncoding region (NCR) of genomes of picornaviruses belonging to the Cardio - and Aphthovirus genera over 50 years ago, but the molecular basis of their function is still unknown. Truncation or complete deletion of the polyC tracts in picornaviruses compromises virulence and pathogenicity but do not affect replicative fitness in vitro, suggesting a role as “viral security” RNA element. The evidence available suggests that the presence of a long polyC tract is required for replication in immune cells, which impacts viral distribution and targeting, and, consequently, pathogenic progression. Viral attenuation achieved by reduction of the polyC tract length has been successfully used for vaccine strategies. Further elucidation of the role of the polyC tract in viral replication cycle and its connection with replication in immune cells has the potential to expand the arsenal of tools in the fight against cancer in oncolytic virotherapy (OV). Here, we review the published data on the biological significance and mechanisms of action of the polyC tract in viral pathogenesis in Cardio - and Aphthoviruses .

Polyvinylpyrrolidone/1-triacontene (PVP/TA) copolymer fibre webs produced by centrifugal melt spinning were studied to determine the influence of jet rotation speed on morphology and internal structure as well as their potential utility as adsorbent capture media for disperse dye effluents. Fibres were produced at 72 °C with jet head rotation speeds from 7000 to 15,000 r min⁻¹. The fibres were characterised by means of SEM, XRD and DSC. Adsorption behaviour was investigated by means of an isothermal bottle point adsorption study using a commercial disperse dye, Dianix AC-E. Through centrifugal spinning nanofibers and microfibers could be produced with individual fibres as fine as 200–300 nm and mean fibre diameters of ca. 1–2 µm. The PVP/TA fibres were mechanically brittle with characteristic brittle tensile fracture regions observed at the fibre ends. DSC and XRD analyses suggested that this brittleness was linked to the graft chain crystallisation where the PVP/TA was in the form of a radial brush copolymer. In this structure, the triacontene branches interlock and form small lateral crystals around an amorphous backbone. As an adsorbent, the PVP/TA fibres were found to adsorb 35.4 mg g⁻¹ compared to a benchmark figure of 30.0 mg g⁻¹ for a granular-activated carbon adsorbent under the same application conditions. PVP/TA is highly hydrophobic and adsorbs disperse dyes through the strong “hydrophobic bonding” interaction. Such fibrous assemblies may have applications in the targeted adsorption and separation of non-polar species from aqueous or polar environments.

Over the last two decades, the utilization of various novel therapies in the upfront or salvage settings has continued to improve survival outcomes for patients with Multiple Myeloma (MM). Thus, the conventional role for hematopoietic stem cell transplantation (HSCT) in MM either in the form of an autologous stem cell transplant (ASCT) or an allogeneic stem cell transplant (Allo-SCT) warrants re-evaluation, given the aforementioned clinical advances. Here, we present a consensus statement of our multidisciplinary group of over 30 Mayo Clinic physicians with a special interest in the care of patients with MM and provide evidence-based recommendations on the use of HSCT in MM. We specifically address topics that include the role and timing of an ASCT for MM in the era of novel agents, eligibility for an ASCT, post-ASCT consolidation, and maintenance options, and finally the utility of an upfront tandem ASCT, salvage second ASCT, and an allo-SCT in MM.

The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo . We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients.

Background Long-lasting insecticidal nets (LLINs) are expected to last for at least 3 years, but whilst this may be achieved from an insecticidal perspective, physical protection is frequently compromised much earlier because of the rapid accumulation of holes during use. To understand why LLINs are so susceptible to loss of physical integrity, thousands of hole damage sites in LLINs retrieved from the field in Africa and Asia were forensically studied to identify the persistent underlying causes. Methods A total of 525 LLINs consisting of six different brands from five different countries across Africa and Asia were collected from the field after 1 to 3 years in use. More than 42,000 individual sites of hole damage were analysed based on the morphology and size of each individual hole, aided by optical microscopy (OM) and scanning electron microscopy (SEM). The fracture morphology enabled positive identification of the underlying mechanisms of the damage. Results Across all LLINs and geographical settings, mechanical damage is the primary cause of holes and loss of physical integrity in LLINs (63.14% by frequency and 81.52% by area). Snagging is the single most frequent mechanical damage mechanism, whilst the largest sized holes in LLINs result from seam failure and tearing. Abrasion and hole enlargement are also responsible for a progressive loss in the physical integrity of nets. Collectively, these five modes of mechanical damage can be expected to result from normal use of LLINs by households. Evidence of deliberate cutting, burn holes and rodent damage was observed to a lesser degree, which LLINs are not designed to withstand. Conclusions Loss of physical integrity in LLINs is an inevitable consequence of using a vector control product that has an inherently low resistance to mechanical damage during normal use. To improve performance, new specifications based on laboratory textile testing is needed, to assess the resistance of LLIN products to the primary causes of mechanical damage when in use, which are snagging, tearing, abrasion and hole enlargement. Seam construction also needs to meet a revised minimum standard to reduce the risk of a rapid loss of physical integrity during use.