scholarly journals Blood-brain barrier disruption with low-intensity pulsed ultrasound for the treatment of pediatric brain tumors: a review and perspectives

2020 ◽  
Vol 48 (1) ◽  
pp. E10 ◽  
Author(s):  
Kévin Beccaria ◽  
Michael Canney ◽  
Guillaume Bouchoux ◽  
Stéphanie Puget ◽  
Jacques Grill ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Clinical Trials ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Pediatric Brain Tumors ◽  
Brain Barrier ◽  
Pulsed Ultrasound ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Pediatric Brain

Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.

Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models

2021 ◽  
pp. clincanres.3760.2020
Author(s):  
Aria Sabbagh ◽  
Kevin Beccaria ◽  
Xiaoyang Ling ◽  
Anantha Marisetty ◽  
Martina Ott ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Pulsed Ultrasound ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Blood Brain

scholarly journals SCIDOT-23. LOW INTENSITY PULSED ULTRASOUND ENHANCES BLOOD-BRAIN BARRIER OPENING AND IMPROVES RESPONSE TO IMMUNOTHERAPY FOR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi276-vi276
Author(s):  
Aria Sabbagh ◽  
Anantha Marisetty ◽  
Martina Ott ◽  
Xiaoyang Ling ◽  
Emily Barton ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Cell Delivery ◽  
Pulsed Ultrasound ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Car T Cell ◽  
Car T

Abstract The blood-brain barrier (BBB) is a significant obstruction to the delivery of treatments for glioblastoma. Previous studies have demonstrated the use of Low Intensity Pulsed Ultrasound (LIPU) in combination with microbubbles as a safe and therapeutic method for temporary BBB disruption to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma. Glioblastoma has minimal T cell infiltration. In this work, we investigated if LIPU sonications (1 MHz, 0.3 MPa, 120 s duration) could enhance T cell delivery to the tumor microenvironment and enhance immunotherapy. NSG mice with established EGFRvIII+U87 tumors were treated intravenously with bioluminescent labeled epidermal growth factor receptor variant III (EGFRvIII) expressing chimeric antigen receptor (CAR) T cells with and without ultrasound BBB disruption. Combining systemic CAR T cell administration with ultrasound BBB disruption, resulted in a significant increase in CAR T cell delivery to the mouse CNS after 12 (p<0.005) and 24 hours (p<0.001) associated with enhanced median survival. In a second murine model of C57BL/6 mice bearing intracerebrally implanted GL261 gliomas, mice treated with anti-PD-1 and ultrasound BBB disruption survived 58 days relative to 39 days of mice treated with only anti-PD-1. Long-term survivors in the anti-PD-1 and anti-PD-1+ ultrasound treatment groups all remained alive after contralateral hemisphere rechallenge with GL261 glioma cells. LIPU-induced BBB disruption increases the delivery of immune therapeutics to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies to the clinic.

Overcoming the Blood-Brain Barrier in Chemotherapy Treatment of Pediatric Brain Tumors

2013 ◽  
Vol 31 (3) ◽  
pp. 531-540 ◽  
Author(s):  
Linfeng Wu ◽  
Xiaoxun Li ◽  
Dileep R. Janagam ◽  
Tao L. Lowe
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Pediatric Brain Tumors ◽  
Brain Barrier ◽  
Chemotherapy Treatment ◽  
Blood Brain ◽  
Pediatric Brain

scholarly journals Blood-brain barrier–adapted precision medicine therapy for pediatric brain tumors

2017 ◽  
Vol 188 ◽  
pp. 27.e1-27.e14 ◽  
Author(s):  
Bernard L. Marini ◽  
Lydia L. Benitez ◽  
Andrew H. Zureick ◽  
Ralph Salloum ◽  
Angela C. Gauthier ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Precision Medicine ◽  
Blood Brain Barrier ◽  
Pediatric Brain Tumors ◽  
Brain Barrier ◽  
Blood Brain ◽  
Pediatric Brain

scholarly journals Complementary role of mathematical modeling in preclinical glioblastoma: differentiating poor drug delivery from drug insensitivity

2021 ◽  
Author(s):  
Javier C. Urcuyo ◽  
Susan Christine Massey ◽  
Andrea Hawkins-Daarud ◽  
Bianca-Maria Marin ◽  
Danielle M. Burgenske ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Drug Delivery ◽  
Clinical Trials ◽  
Treatment Response ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Significant Heterogeneity ◽  
Current Standard ◽  
Modeling Approach ◽  
Blood Brain

AbstractGlioblastoma is the most malignant primary brain tumor with significant heterogeneity and a limited number of effective therapeutic options. Many investigational targeted therapies have failed in clinical trials, but it remains unclear if this results from insensitivity to therapy or poor drug delivery across the blood-brain barrier. Using well-established EGFR-amplified patient-derived xenograft (PDX) cell lines, we investigated this question using an EGFR-directed therapy. With only bioluminescence imaging, we used a mathematical model to quantify the heterogeneous treatment response across the three PDX lines (GBM6, GBM12, GBM39). Our model estimated the primary cause of intracranial treatment response for each of the lines, and these findings were validated with parallel experimental efforts. This mathematical modeling approach can be used as a useful complementary tool that can be widely applied to many more PDX lines. This has the potential to further inform experimental efforts and reduce the cost and time necessary to make experimental conclusions.Author summaryGlioblastoma is a deadly brain cancer that is difficult to treat. New therapies often fail to surpass the current standard of care during clinical trials. This can be attributed to both the vast heterogeneity of the disease and the blood-brain barrier, which may or may not be disrupted in various regions of tumors. Thus, while some cancer cells may develop insensitivity in the presence of a drug due to heterogeneity, other tumor areas are simply not exposed to the drug. Being able to understand to what extent each of these is driving clinical trial results in individuals may be key to advancing novel therapies. To address this challenge, we used mathematical modeling to study the differences between three patient-derived tumors in mice. With our unique approach, we identified the reason for treatment failure in each patient tumor. These results were validated through rigorous and time-consuming experiments, but our mathematical modeling approach allows for a cheaper, quicker, and widely applicable way to come to similar conclusions.

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