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High-Affinity DARPin Allows Targeting of MeV to Glioblastoma Multiforme in Combination with Protease Targeting without Loss of Potency.

Measles virus (MeV) is naturally cytolytic by extensive cell-to-cell fusion. Vaccine-derived MeV is toxic for cancer cells and is clinically tested as oncolytic virus. To combine the potential of MeV with enhanced safety, different targeting strategies have been described. We generated a receptor-targeted MeV by using receptor-blind viral attachment protein genetically fused to designed ankyrin repeat protein (DARPin) binding domains specific for the epidermal growth factor receptor (EGFR). To reduce on-target toxicity for EGFR+ healthy cells, we used an engineered viral fusion protein activat

Decoding the molecular mechanisms of pyroptosis and its therapeutic development prospects.

Pyroptosis is an emerging form of inflammatory programmed cell death primarily mediated by the gasdermin protein family, characterized by cell swelling, membrane pore formation, and the release of pro-inflammatory cytokines such as IL-1β and IL-18. This mode of cell death has garnered significant attention due to its critical involvement in a variety of diseases, including cancer, cardiovascular disorders, autoimmune diseases, and metabolic syndromes, positioning it as a promising therapeutic target. Despite advances, the complexity of pyroptosis regulation and its dual roles in disease pathog

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… Similarly, vesicular stomatitis virus (VSV)-mediated pyroptosis sensitized immunologically cold tumors to checkpoint blockade by recruiting cytotoxic lymphocytes ( Lin et al., 2022 ). …

Ось miR4261/PAMM в множестве миэломы стимулирует ресорбцию костей.

В рамках этого исследования изучаются механизмы, лежащие в основе заболевания костями миэломы (МБД) в множестве миеломы (МММ), с уделением особого внимания экзосомам миеломы и жидким биопсическим биомаркерам в целях выявления терапевтических целей для снижения остеокластной активности и усиления гомеостазиза костей. Совместная культурная деятельность ОПМ2, РПМ 8226, и NCI-H929 линии миэломы THP-1 Клетки использовались для оценки miR4261 и перокса ироксина, активированного в M-CSF-стимулированных моноцитах (PAMM) через RT-qPCR. Двухлюсиферазы подтвердили, что miR4261 связывает 3Непереведенная о

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… For each construct, a DNA mixture was prepared in 250 µL of Opti-MEM containing 6 µg of the lentiviral vector plasmid, along with the packaging plasmids: 3.9 µg of ΔR, 1.5 µg of REV, and 2.1 µg of vesicular stomatitis virus glycoprotein (VSV-G) envelope plasmid. …

Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation.

Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, incl

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… TLR7 and TLR8 recognize single-stranded RNA viruses such as vesicular stomatitis virus and the influenza virus [ 55 , 56 ]. TLR9 is required for the response to microbial unmethylated CpG DNA [ 57 , 58 ]. …

Emerging strategies and therapies for treatment of Paget's disease of bone.

Paget's disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemi

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… Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity. 2009;30(4):588–598. doi: 10.1016/j.immuni.2009.02.009. 81. Seglen PO, Bohley P. Autophagy and other vacuolar protein degradation mechanisms. …

Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) ba

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… LV Production and Purification LVs were produced in HEK293T cells, using the four-plasmid system, as previously described. 119 HIV-1 vectors were pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G) envelope, concentrated by ultracentrifugation, and resuspended in PBS (GIBCO, Life Technologies …

Связанный с K27 ROR__t Уничтожение Nedd4 потенциалами Th17-посредованная автонепроницаемость.

СПРАВОЧНАЯ ИНФОРМАЦИЯ: Было продемонстрировано, что THCT E3 Ubriquitin ligase Nedd4 позитивно регулирует реакцию клеток Т, однако его роль в дифференциации клеток и автономном иммунитете Т неизвестна. Считается, что 17 клеток играют ключевую роль в развитии и патогенезе аутоиммунных заболеваний. Тем не менее, правила, регулирующие активацию РОРТ в ходе дифференциации клеток TH17 с помощью сигнала TCR, пока еще не уточнены. Эти неизведанные аспекты вдохновляют нас на изучение потенциальной роли Nedd4 в автоматическом иммунитете Th17.МЕТОДЫ: Мы провели оценку воздействия дефицита Nedd4 на развит

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… HEK293T were transiently co-transfected with pRV-3 GFP encoding GFP tagged RORγt or RORγt K112R expression vectors together with (pHEP and pENV) packaging plasmids containing vesicular stomatitis virus G protein (VSV-G) by using calcium precipitation. …

Viral Vector-Based Melanoma Gene Therapy.

Gene therapy applications of oncolytic viruses represent an attractive alternative for cancer treatment. A broad range of oncolytic viruses, including adenoviruses, adeno-associated viruses, alphaviruses, herpes simplex viruses, retroviruses, lentiviruses, rhabdoviruses, reoviruses, measles virus, Newcastle disease virus, picornaviruses and poxviruses, have been used in diverse preclinical and clinical studies for the treatment of various diseases, including colon, head-and-neck, prostate and breast cancer as well as squamous cell carcinoma and glioma. The majority of studies have focused on i

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… In order to reduce the environmental risk of NDV, which is toxic in birds, and the neurotoxicity of VSV (Vesicular stomatitis virus), a hybrid vector was engineered, where the VSV G protein was replaced with NDV hemagglutinin-neuraminidase (HN) and further modified by fusion proteins. …

Immune-based cancer therapies: mechanistic insights, clinical progress, and future directions.

The field of cancer immunotherapy has evolved rapidly, offering new treatment paradigms by harnessing the body's own immune system to target and destroy malignancies. Various immunotherapeutic approaches, including immune checkpoint inhibitors, CAR-T cell therapy, cancer vaccines, cytokine therapies, and oncolytic viruses, have shown significant promise in treating different cancer types. This review provides a comprehensive examination of the historical development and recent advances in cancer immunotherapy. We discuss the mechanisms of action of key immunotherapeutic modalities, along with

CAR-T cell therapy: Where are we now, and where are we heading?

Chimeric antigen receptor (CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies, with 9 CAR-T-cell products currently available. Furthermore, CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas, including solid tumors, myocardial fibrosis, and autoimmune and infectious diseases. Despite these advancements, significant challenges pertaining to treatment-related toxic reactions and relapses persist. Consequently, current research efforts are focused on addressing these issues to enhance the safe

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… Evgin et al loaded CAR-T cells with vesicular stomatitis or eutherian virus for treating solid tumors in mouse models. Systemic delivery greatly enhanced the efficacy of CAR-T cells in treating melanoma and glioma tumors and improved survival. 155 4. …

Beyond Formulation: Contributions of Nanotechnology for Translation of Anticancer Natural Products into New Drugs.

Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, which is quite curious since the research and development (R&D) course of nanoformulations are even more expensive and prone to failure than the conventional ones. Nonetheless, nanosystems are cost-effective and represent both novel and safer dosage forms with fewer side effects due to m

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Lung cancer immunotherapy: progress, pitfalls, and promises.

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are

Oncolytic virus therapy in the elderly: immune frailty, challenges, and perspectives.

With global aging accelerating, cancer incidence among older adults is rapidly increasing. Individuals aged ≥65 years now represent 64% of new cancer cases and 71.3% of cancer-related deaths worldwide. This population exhibits a distinct immune imbalance-driven by tumor-induced immunosuppression, immunosenescence, and inflammaging-which contributes to poor tolerance of standard therapies and suboptimal outcomes with PD-1/PD-L1 inhibitors. As an emerging immunotherapeutic strategy, oncolytic viruses (OVs) selectively infect tumor cells, induce immunogenic cell death (ICD), and activate the cGAS

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… A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses . …

Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial.

PurposeOur preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen.Patients and methodsPatients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on D

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… Oncolytic viruses represent attractive priming agents due to general tolerability, and several oncolytic viruses are being examined in multiple myeloma in ongoing clinical trials, including PELA, measles virus ( NCT00450814 and NCT02192775 ), and vesicular stomatitis virus ( NCT00450814 ; ref. 45 ). …

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues f

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… Care must be taken however, as application of a vesicular stomatitis virus encoding IFNβ resulted in the reverse outcome on CAR T cells targeting EGFRvIII in B16 murine glioma tumors ( 121 ). …

Harnessing the Immune System to Fight Multiple Myeloma.

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy differing substantially in clinical behavior, prognosis, and response to treatment. With the advent of novel therapies, many patients achieve long-lasting remissions, but some experience aggressive and treatment refractory relapses. So far, MM is considered incurable. Myeloma pathogenesis can broadly be explained by two interacting mechanisms, intraclonal evolution of cancer cells and development of an immunosuppressive tumor microenvironment. Failures in isotype class switching and somatic hypermutations result in the neoplastic

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… Recently reported results of a phase 1 trial, NCT03017820 , showed that systemic administration of genetically modified vesicular stomatitis virus (VSV) to patients with heavily pretreated hematological malignancies did not induce any objective responses in MM patients, however, responses have been observed …

Targeting cytokine and chemokine signaling pathways for cancer therapy.

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and o

T-cell engagers in cancer immunotherapy: mechanisms, challenges, and future perspectives.

T-cell engagers (TCEs) are a rapidly evolving class of cancer immunotherapies that redirect cytotoxic T cells to tumor-associated antigens independently of MHC presentation. This review outlines the development, structural formats, and therapeutic potential of various TCE platforms, including bispecific (BiTEs) and trispecific T-cell engagers (TriTEs), dual affinity re-targeting (DART), and other emerging formats. We also highlight the clinical success in treating hematologic malignancies as demonstrated by agents such as blinatumomab and teclistamab. We also discussed the ongoing challenges i

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… One notable example is the oncolytic rhabdovirus vesicular stomatitis virus (VSVΔ51), which is engineered to express a truncated HER2 antigen (HER2T). …

Constructing the cure: engineering the next wave of antibody and cellular immune therapies.

Immuno-oncology has revolutionized cancer treatment by mobilizing the immune system to eliminate tumors. Although immune checkpoint inhibitors and T cell therapies have mediated durable responses in hematologic malignancies and select solid tumors, most patients still relapse or fail to respond. To overcome these limitations, novel, next-generation immune constructs, including bispecific-cell therapy combinations, armored cells, tethered cytokines, immune-stimulatory antibody conjugates, and in vivo gene editing, are being developed to enhance specificity, persistence, and immune activation. T