scholarly journals Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna Galstyan ◽  
Janet L. Markman ◽  
Ekaterina S. Shatalova ◽  
Antonella Chiechi ◽  
Alan J. Korman ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Brain Tumor ◽  
Blood Brain Barrier ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Brain Barrier ◽  
Systemic Delivery ◽  
Blood Brain

AbstractBrain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood–brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

scholarly journals Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment

2018 ◽  
Author(s):  
Anna Galstyan ◽  
Antonella Chiechi ◽  
Alan J. Korman ◽  
Tao Sun ◽  
Liron L. Israel ◽  
...  
Keyword(s):  
Immune Response ◽  
Brain Tumor ◽  
Blood Brain Barrier ◽  
T Regulatory Cells ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Brain Barrier ◽  
Blood Brain ◽  
Local Brain

AbstractTreatment of brain gliomas with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross the blood-brain barrier (BBB). We describe a new generation of nano immunoconjugates (NICs) developed on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response in glioma-bearing mice. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) resulted in an increase of CD8+ T-cells with a decrease of T regulatory cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local brain tumor immune response.

scholarly journals Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1294
Author(s):  
Yogesh R. Suryawanshi ◽  
Autumn J. Schulze
Keyword(s):  
Immune Responses ◽  
Malignant Glioma ◽  
Blood Brain Barrier ◽  
Tumor Heterogeneity ◽  
Checkpoint Inhibitors ◽  
Oncolytic Viruses ◽  
Brain Barrier ◽  
Current Status ◽  
Blood Brain ◽  
Federal Authority

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood–brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood–brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

scholarly journals Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

2017 ◽  
Vol 89 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Jonathan I Spencer ◽  
Jack S Bell ◽  
Gabriele C DeLuca
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Specific Immune Response ◽  
Brain Barrier ◽  
Vascular Pathology ◽  
Current Evidence ◽  
Blood Brain

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

scholarly journals Examination of blood–brain barrier (BBB) integrity in a mouse brain tumor model

2012 ◽  
Vol 111 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Ngoc H. On ◽  
Ryan Mitchell ◽  
Sanjot D. Savant ◽  
Corbin. J. Bachmeier ◽  
Grant M. Hatch ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Tumor Model ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Tumor Model

Permeability of PEGylated Immunoarsonoliposomes Through In Vitro Blood Brain Barrier-Medulloblastoma Co-culture Models for Brain Tumor Therapy

2014 ◽  
Vol 32 (3) ◽  
pp. 1072-1083 ◽  
Author(s):  
Abdulghani Al-Shehri ◽  
Marco E. Favretto ◽  
Panayiotis V. Ioannou ◽  
Ignacio A. Romero ◽  
Pierre-Olivier Couraud ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Blood Brain Barrier ◽  
Tumor Therapy ◽  
Brain Barrier ◽  
Blood Brain ◽  
Culture Models ◽  
Brain Tumor Therapy
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