Despite significant advances in our knowledge regarding the genetics and molecular biology of gliomas over the past two decades and hundreds of clinical trials, no effective therapeutic approach has been identified for adult patients with newly diagnosed glioblastoma, and overall survival remains dismal. Great hopes are now placed on combination immunotherapy. In clinical trials, immunotherapeutics are generally tested after standard therapy (radiation, temozolomide, and steroid dexamethasone) or concurrently with temozolomide and/or steroids. Only a minor subset of patients with progressive/recurrent glioblastoma have benefited from immunotherapies. In this review, we comprehensively discuss standard therapy-related systemic immunosuppression and lymphopenia, their prognostic significance, and the implications for immunotherapy/oncolytic virotherapy. The effectiveness of immunotherapy and oncolytic virotherapy (viro-immunotherapy) critically depends on the activity of the host immune cells. The absolute counts, ratios, and functional states of different circulating and tumor-infiltrating immune cell subsets determine the net immune fitness of patients with cancer and may have various effects on tumor progression, therapeutic response, and survival outcomes. Although different immunosuppressive mechanisms operate in patients with glioblastoma/gliomas at presentation, the immunological competence of patients may be significantly compromised by standard therapy, exacerbating tumor-related systemic immunosuppression. Standard therapy affects diverse immune cell subsets, including dendritic, CD4+, CD8+, natural killer (NK), NKT, macrophage, neutrophil, and myeloid-derived suppressor cell (MDSC). Systemic immunosuppression and lymphopenia limit the immune system’s ability to target glioblastoma. Changes in the standard therapy are required to increase the success of immunotherapies. Steroid use, high neutrophil-to-lymphocyte ratio (NLR), and low post-treatment total lymphocyte count (TLC) are significant prognostic factors for shorter survival in patients with glioblastoma in retrospective studies; however, these clinically relevant variables are rarely reported and correlated with response and survival in immunotherapy studies (e.g., immune checkpoint inhibitors, vaccines, and oncolytic viruses). Our analysis should help in the development of a more rational clinical trial design and decision-making regarding the treatment to potentially improve the efficacy of immunotherapy or oncolytic virotherapy.
To evaluate the effect of fractionated radiotherapy on permeability of the blood-brain barrier in healthy rats and rats with C6 glioma in vivo.An increase in BBB permeability in C6 glioma was assessed by dynamic MRI monitoring (glioma size before and after radiation therapy in combination with immunotherapy, n=30) and confocal microscopy (fluorescence imaging of tumor invasion boundaries in a dose-dependent experiment for the amount of injected antibodies). In healthy rats, BBB permeability to macromolecular substances (MMS) was assessed by ELISA (n=23, 192 plasma samples) and confocal microscopy (n=7).It was shown that BBB permeability to biological macromolecules in blood-brain and brain-blood directions was increased after fractionated radiotherapy.Drug delivery to the brain can be improved using therapeutic doses of radiation treatment that affects the BBB and minimizes the risk of serious side effects that are often associated with the drug dose.Опухоли головного мозга сопровождаются нарушением функций гематоэнцефалического барьера (ГЭБ), однако поступление лекарственных препаратов в клетки-мишени остается по-прежнему затрудненным. Цель исследования - оценка влияния фракционной радиотерапии на проницаемость гематоэнцефалического барьера на здоровых крысах и крысах с глиомой С6 in vivo. Материал и методы. Увеличение проницаемости ГЭБ при глиоме С6 оценивали методом мониторинга магнитно-резонансной томографии (объем глиомы до и после радиотерапии в комбинации с иммунотерапией, n=30) и конфокальной микроскопии (флуоресцентная визуализация границ опухолевой инвазии в дозозависимом эксперименте по количеству вводимых антител). На здоровых крысах оценку проницаемости ГЭБ для высокомолекулярных соединений проводили методом иммуноферментного анализа ELIZA (n=23; 192 образца плазмы крови) и конфокальной микроскопии (n=7). Результаты. Было показано повышение проницаемости ГЭБ после фракционированной радиотерапии в направлениях 'кровь-мозг' и 'мозг-кровь' для высокомолекулярных биологических молекул. Заключение. Воздействие на ГЭБ облучением в терапевтических дозах может улучшить доставку лекарственных препаратов в головной мозг и тем самым минимизировать риск серьезных побочных явлений, связанных чаще всего с дозой лекарственного средства.
Intra-arterial (IA) mesenchymal stem cells (MSCs) transplantation providing targeted cell delivery to brain tissue is a promising approach to the treatment of neurological disorders, including stroke. Factors determining cell distribution after IA administration have not been fully elucidated. Their decoding may contribute to the improvement of a transplantation technique and facilitate translation of stroke cell therapy into clinical practice. The goal of this work was to quantitatively assess the impact of brain tissue perfusion on the distribution of IA transplanted MSCs in rat brains. We performed a selective MR-perfusion study with bolus IA injection of gadolinium-based contrast agent and subsequent IA transplantation of MSCs in intact rats and rats with experimental stroke and evaluated the correlation between different perfusion parameters and cell distribution estimated by susceptibility weighted imaging (SWI) immediately after cell transplantation. The obtained results revealed a certain correlation between the distribution of IA transplanted MSCs and brain perfusion in both intact rats and rats with experimental stroke with the coefficient of determination up to 30%. It can be concluded that the distribution of MSCs after IA injection can be partially predicted based on cerebral perfusion data, but other factors requiring further investigation also have a significant impact on the fate of transplanted cells.
Hydrophobized and non-hydrophobized Fab fragments of human antibodies against gliofibrillar acid protein (GFAP) and brain specific alpha 2-glycoprotein (alpha 2GP) were used to study their penetration through the blood-brain barrier (BBB). These Fab fragments were modified by stearoyl chloride in reversed micelles of aerosol OT in octane (one or two fatty acid residues attached to protein molecule). Modified and non-modified 125I-labelled Fab fragments were intracardially administered to rats. The amount of label accumulated in brain was 55% higher than the total amount in all other organs. In contrast, non-hydrophobized Fab fragments did not penetrate through the BBB. We assume that the artificial hydrophobization of Fab fragments can increase their capability to penetrate through the cell membranes and, in particular, the BBB.
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