Oncolytic viruses have gained momentum in the last decades as a promising tool for cancer treatment. Despite the progress, only a fraction of patients show a positive response to viral therapy. One of the key variable factors contributing to therapy outcomes is interferon-dependent antiviral mechanisms in tumor cells. Here, we evaluated this factor using patient-derived glioblastoma multiforme (GBM) cultures. Cell response to the type I interferons’ (IFNs) stimulation was characterized at mRNA and protein levels. Omics analysis revealed that GBM cells overexpress interferon-stimulated genes (ISGs) and upregulate their proteins, similar to the normal cells. A conserved molecular pattern unambiguously differentiates between the preserved and defective responses. Comparing ISGs’ portraits with titration-based measurements of cell sensitivity to a panel of viruses, the “strength” of IFN-induced resistance acquired by GBM cells was ranked. The study demonstrates that suppressing a single ISG and encoding an essential antiviral protein, does not necessarily increase sensitivity to viruses. Conversely, silencing IFIT3 and PLSCR1 genes in tumor cells can negatively affect the internalization of vesicular stomatitis and Newcastle disease viruses. We present evidence of a complex relationship between the interferon response genes and other factors affecting the sensitivity of tumor cells to viruses.

Background: Canine mastocytomas (mast cell tumors) represent a common malignancy among many dog breeds. A typical treatment strategy for canine mastocytomas includes surgery, chemo- and radio-therapy, although in many cases the therapy fails and the disease progression resumes. New treatment approaches are needed.Aims: The goal of this pilot study was to examine safety and efficacy of oncolytic Sendai virus therapy administered to canine patients with cutaneous or subcutaneous mastocytomas.Materials and Methods: Six canine patients, with variable grades and stages of the disease, received virus therapy, either as a monotherapy, or in combination with surgery. The therapy included two or more virus applications administered weekly or biweekly. Each application of Sendai virus (107-108.6 EID50) consisted of multiple individual 0.01–0.1 ml injections delivered intratumorally, intradermally around a tumor, and under a tumor bed.Results: The treatment was well tolerated, with minor transitory side effects. Of the six dogs, two did not receive surgery or any other treatment besides the virus injections. The other four animals underwent radical or debulking surgeries, and in three of them the subsequent administration of Sendai virus completely cleared locally recurrent or/and remaining tumor masses. Five dogs demonstrated a complete response to the treatment, the animals remained disease free during the time of observation (2–3 years). One dog responded only partially to the virotherapy; its after-surgical recurrent tumor and some, but not all, metastases were cleared. This dog had the most advanced stage of the disease with multiple enlarged lymph nodes and cutaneous metastases.Conclusion: The results of the pilot study suggest that Sendai virus injections could be safe and efficient for the treatment of dogs affected by mastocytomas.They also suggest the need of further studies for finding optimal schemes and schedules for this kind of therapy.

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Основным источником возникновения рецидивов мультиформной глиобластомы после хирургического вмешательства являются стволовые клетки, успевающие проникнуть глубоко в ткани мозга. В настоящее время актуален поиск новых подходов для борьбы с ними, в том числе с помощью онколитических вирусов. Целью работы было определение чувствительности к непатогенным энтеровирусам клеток мультиформной глиобластомы человека, поддерживаемых in vitro и в модели мышиных ксенотрансплантатов. Культуры опухолевых клеток глиобластом испытывали на чувствительность к полиовирусу 1 типа (штамм вакцины Сэбина), вирусу Коксаки A7 (штамм ЖЭВ8), Коксаки A9 (штамм ЖЭВ9) и Коксаки B5 (Штамм ЖЭВ12). Количественную оценку репродукции вирусов и их цитолитическую активность проводили заражением монослойных культур клеток глиобластомы. Эффективность уничтожения стволовых клеток глиобластомы определяли по способности клеточных культур глиобластом, обогащенных опухолевыми стволовыми клетками, формировать подкожные опухоли у иммунодефицитных мышей после обработки вирусами. По результатам исследования наиболее выраженная онколитическая и репликационная активность выявлена у вируса Коксаки A7 и полиовируса 1 типа при тестировании в модели культур клеток глиобластом, инфицированных вирусами in vitro, а также in vivo, в модели подкожных опухолевых ксенотрансплантатов на иммунодефицитных мышах. Полиовирус 1 типа и вирус Коксакси A7 предотвращали образование опухолей после того как нейросферные культуры клеток глиобластом преинкубировали с вирусами перед подкожным введением. Вирус Коксаки В5 вызывал лишь частичное сокращение числа опухолей, а Коксаки A9 не влиял на опухолеобразование. Таким образом, ряд штаммов непатогенных энтеровирусов способен уничтожать стволовые клетки глиобластом и представляется перспективным при разработке терапевтических средств для безрецидивного лечения глиобластом.Ключевые слова: мультиформная глиобластома, онколитический вирус, непатогенные энтеровирусы, персонифицированная медицина, рецидив опухоли, экспериментальная терапия рака HUMAN ENTEROVIRUSES EXHIBIT SELECTIVE ONCOLYTIC ACTIVITY IN THE MODEL OF HUMAN GLIOBLASTOMA MULTIFORME XENOGRAFTS IN IMMUNODEFICIENT MICEStem cells that penetrated deeply into the brain tissue are the main reason behind the relapses of glioblastoma multiforme after surgery.Finding new approaches to counter such relapses, including those that make use of oncolytic viruses, is a pressing issue. This study aimed to determine the sensitivity of cells of human glioblastoma multiforme to non-pathogenic enteroviruses, in vitro and in vivo (mice xenografts model). Glioblastoma tumor cells were exposed to type 1 poliovirus (Sabin vaccine strain), Coxsackie virus A7 (strain LEV8), Coxsackie virus A9 (strain LEV9) and Coxsackie virus B5 (strain LEV14). The virus reproduction intensity and cytolytic activity were assessed through infection of monolayered glioblastoma cell cultures. The ability of glialoblastoma cell cultures (enriched with tumor stem cells) to build subcutaneous tumors in immunodeficient mice afte...