Glioblastoma is the most aggressive form of malignant brain tumor. Standard treatment protocols and traditional immunotherapy are poorly effective as they do not significantly increase the long-term survival of glioblastoma patients. Oncolytic viruses (OVs) may be an effective alternative approach. Combining OVs with some modern treatment options may also provide significant benefits for glioblastoma patients. Here we review virotherapy for glioblastomas and describe several OVs and their combination with other therapies. The personalized use of OVs and their combination with other treatment options would become a significant area of research aiming to develop the most effective treatment regimens for glioblastomas.
Cancer cell lines responded differentially to type I interferon treatment in models of oncolytic therapy using vesicular stomatitis virus (VSV). Two opposite cases were considered in this study, glioblastoma DBTRG-05MG and osteosarcoma HOS cell lines exhibiting resistance and sensitivity to VSV after the treatment, respectively. Type I interferon responses were compared for these cell lines by integrative analysis of the transcriptome, proteome, and RNA editome to identify molecular factors determining differential effects observed. Adenosine-to-inosine RNA editing was equally induced in both cell lines. However, transcriptome analysis showed that the number of differentially expressed genes was much higher in DBTRG-05MG with a specific enrichment in inflammatory proteins. Further, it was found that two genes, EGFR and HER2, were overexpressed in HOS cells compared with DBTRG-05MG, supporting recent reports that EGF receptor signaling attenuates interferon responses via HER2 co-receptor activity. Accordingly, combined treatment of cells with EGF receptor inhibitors such as gefitinib and type I interferon increases the resistance of sensitive cell lines to VSV. Moreover, sensitive cell lines had increased levels of HER2 protein compared with non-sensitive DBTRG-05MG. Presumably, the level of this protein expression in tumor cells might be a predictive biomarker of their resistance to oncolytic viral therapy.
Diffuse gliomas are incurable, prevalent, and aggressive central nervous system tumors. Therefore, the development of selective oncolytic viral strains for malignant neoplasms is highly relevant. This study aimed to create an oncolytic virus based on a vaccine strain of poliovirus type 3 with natural antitumor activity. To achieve this goal, we replaced the internal ribosome entry site (IRES) of poliovirus with the corresponding fragment of human rhinovirus 30. The resulting recombinant oncolytic strain RVP3 retained the serotype of poliovirus type 3, as confirmed by virus neutralization micro-test with specific antiserum. In addition, the oncolytic efficacy of RVP3 was assessed in vitro on a broad panel of cell cultures. According to the results, RVP3 has changed its tropism, losing the ability to replicate in conditionally normal cell lines of embryonic astrocytes and embryonic fibroblasts while retaining the ability to replicate in tumor cells.
Recombinant herpesviruses can be used as oncolytic therapeutic agents and high packaging capacity vectors for delivering expression cassettes into the cell. Herpesvirus saimiri is a gamma-herpesvirus that normally infects squirrel monkeys but also has a unique ability to infect and immortalize human lymphocytes while allowing them to retain their mature phenotype and functional activity. Recombination of the Herpesvirus saimiri genome in permissive cells is impeded by its resistance to chemical transfection and electroporation. The aim of this study was to develop an effective method for incorporating expression cassettes into the genome of Herpesvirus saimiri without having to transfect a permissive cell culture. Transfected HEK-293T cells expressing glycoproteins of the measles virus vaccine strain were co-cultured with permissive OMK cells infected with Herpesvirus saimiri. Cell fusion and formation of syncytia stimulated recombination between the viral genome and the expression cassette; this allowed us to obtain a recombinant Herpesvirus saimiri variant without chemical transfection in permissive cells. The genetically modified virus expressed a selectable marker and retained its ability to persist in the cell in the latent state; it also caused immortalization of primary lymphoid cells. The proposed approach allows engineering recombinant Herpesvirus saimiri strains carrying a variety of expression cassettes in its genome.Рекомбинантные герпесвирусы можно применять в качестве терапевтических агентов-онколитиков, а также в качестве векторов большой емкости для доставки протяженных экспрессионных конструкций в клетки. Гамма-герпесвирус беличьих обезьян Herpesvirus saimiri обладает уникальной способностью инфицировать человеческие лимфоциты и вызывать их иммортализацию при сохранении зрелого фенотипа и функциональной активности. Проведение рекомбинации генома Herpesvirus saimiri в пермиссивной клеточной культуре затруднено из-за ее устойчивости к химической трансфекции и электропорации. Целью работы являлась разработка эффективного способа введения экспрессионных кассет в геном Herpesvirus saimiri без проведения трансфекции пермиссивной клеточной культуры. Для этого мы использовали совместную культивацию трансфицированных клеток HEK-293T, экспрессирующих также гликопротеины вакцинного штамма вируса кори, и инфицированных Herpesvirus saimiri пермиссивных клеток линии ОМК. Слияние клеток и образование синцитиев привели к запуску рекомбинации между вирусным геномом и экспрессионной кассетой, что позволило получить рекомбинантный вариант Herpesvirus saimiri без необходимости проведения химической трансфекции пермиссивных клеток. Трансгенный вариант вируса характеризовался стабильной экспрессией селективного маркера и сохранял способность персистировать в клеточной культуре в латентной форме, а также вызывать иммортализацию первичных лимфоидных клеток. Примененный метод позволяет в короткие сроки получать рекомбинантные варианты Herpesvirus saimiri с введенными в геном разнообразными экспрессионными кассетами.Ключе...
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