Cancer Letters

Cancer Letters

Volume 479, 1 June 2020, Pages 13-22
Cancer Letters

Ultrasound-induced blood-brain barrier disruption for the treatment of gliomas and other primary CNS tumors

https://doi.org/10.1016/j.canlet.2020.02.013Get rights and content

Highlights

  • The blood-brain barrier prevents most drug therapies from reaching brain tumors.

  • Low-intensity pulsed ultrasound with systemic microbubbles can open the blood-brain barrier.

  • Opening of the blood-brain barrier with ultrasound is safe, localized and reversible.

  • A large panel of therapeutic agents can be delivered to the brain with ultrasound.

  • Extracranial and implantable ultrasound devices are currently in clinical trials.

Abstract

The treatment of primary brain tumors, especially malignant gliomas, remains challenging. The failure of most treatments for this disease is partially explained by the blood-brain barrier (BBB), which prevents circulating molecules from entering the brain parenchyma. Ultrasound-induced BBB disruption (US-BBBD) has recently emerged as a promising strategy to improve the delivery of therapeutic agents to brain tumors. A large body of preclinical studies has demonstrated that the association of low-intensity pulsed ultrasound with intravenous microbubbles can transiently open the BBB in a localized manner. The safety of this technique has been assessed in numerous preclinical studies in both small and large animal models. A large panel of therapeutic agents have been delivered to the brain in preclinical models, demonstrating both tumor control and increased survival. This technique has recently entered clinical trials with encouraging preliminary data. In this review, we describe the mechanisms and histological effects of US-BBBD and summarize the preclinical studies published to date. We furthermore provide an overview of the current clinical development and future potential of this promising technology.

Introduction

Primary brain tumors are the primary cause of solid cancer in the pediatric population, the third cause in young adults and the eighth one in adults older than 40 years old [1]. Mortality rates were estimated at 0.72 per 100,000, 0.96 per 100,000 and 9.01 per 100,000 people in these age groups, respectively, between 2011 and 2015 in the United States [1]. The most common of all malignant brain and other central nervous system (CNS) tumors are high-grade gliomas. These tumors have a particularly dismal prognosis in both children and adults, with 5-year survival rates of less than 20% in children [2] and around 5% in adults [1]. Although important advances have been made in our understanding of these tumors over the last decade, current treatment options remain limited and largely ineffective. Standard treatment of high-grade gliomas is based on maximal surgical resection, followed by adjuvant radiotherapy and chemotherapy. However, the diffuse and infiltrative nature of these tumors limits the efficacy of these treatments. Furthermore, total resection of these tumors is nearly impossible due to the infiltration of cancerous cells into the surrounding healthy tissues and the existence of the blood-brain barrier (BBB), which prevents the majority of systemic drug therapies from reaching the brain.

The BBB is a physiological barrier that protects the brain from potential toxins circulating in the systemic circulation. It is comprised of a system of tight junctions and transport proteins that prevent approximately 98% of small-molecule drugs (<0.5 kD) and 100% of large-molecule drugs from crossing the intact BBB [3]. Thus, most existing and novel therapeutics for brain diseases cannot cross the intact BBB and be delivered to the brain [4]. Although hyperintense on T1w contrast-enhanced magnetic resonance imaging (MRI), showing a partially disrupted BBB, the primary tumor mass (which is typically resected) is surrounded by infiltrative tumor cells, surrounded by an intact BBB [5,6]. These surrounding regions of infiltrative cells lead to recurrence of the tumor in nearly all GBM patients. In other brain tumors, such as medulloblastomas, it has been shown that the permeability of the BBB varied by patient and may have an impact on the response to therapy [7].

Several different methods to disrupt or bypass the BBB have been attempted to improve the delivery of drugs to patients with primary brain tumors. Methods previously tested clinically to increase the permeability of the BBB include mannitol administration to osmotically disrupt the BBB [8] and the use of the bradykinin agonist RMP-7 [9]. Direct injection of drugs into the brain has also been attempted using Rickham/Ommaya reservoirs placed in the ventricle [10] and convection-enhanced delivery devices [11,12]. Despite encouraging results in clinical trials, these methods have not gained widespread clinical use due to the difficulties associated with their routine implementation in the clinic.

An alternative method to enhance the concentrations of drugs in the brain for primary CNS tumors is to use low-intensity pulsed ultrasound (LIPU) in combination with intravenous (IV) injection of microbubbles. This technique, named ultrasound-induced blood-brain barrier disruption (US-BBBD), has been in pre-clinical development for over 20 years [13,14]. This technique has been demonstrated to be safe in a number of small and large animal model systems and preclinical glioma models. Furthermore, US-BBBD has shown efficacy in pre-clinical studies with a range of drug therapies that normally do not cross the BBB and numerous clinical trials have now been initiated within the past five years.

This review focuses on the significant progress made over the past 20 years as the technique of US-BBBD has advanced from a pre-clinical phase to initiation of multiple clinical trials that are now in progress using several different approaches.

Section snippets

Mechanisms

When ultrasound stimulates systemically-administered microbubbles (1–10 μm in diameter), the bubbles expand and contract (a phenomenon called cavitation), inducing mechanical stresses on the capillary walls [15], stimulation of endothelial cells, and temporary BBB disruption (BBBD). Although the exact mechanisms are not fully understood, both mechanical and functional modifications of the BBB may be involved (Fig. 1). Sonication allows for passive diffusion through extracellular pathways by

Safety of US-BBBD in non-human primates

The long-term safety of US-BBBD has been demonstrated in healthy non-human primates (NHP) by several independent teams, with multiple ultrasound approaches and devices.

Marquet et al. and Tung et al. [47,48] disrupted the BBB in male macaque monkeys with a single-element focused ultrasound transducer operating at 500 kHz. By using two types of microbubble agents (Definity® and in-house made microbubbles), they found that MRI contrast enhancement and cavitation response were dependent on the

US-BBBD has been assessed with a large panel of therapeutic agents in different preclinical tumor models

US-BBBD can significantly increase the concentrations of a wide range of systemically administered drugs in healthy brain (hemispheres and brainstem) and brain tumors. Preclinical studies have been performed using low-molecular-weight molecules [[56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73]] and larger molecules such as therapeutic antibodies [[74], [75], [76], [77]] (Table 2). Cell therapies such as natural killer (NK) cells have

Overview of clinical devices

The skull represents the principle obstacle for the application of ultrasound in the field of neuro-oncology. The thick human skull bone distorts and attenuates ultrasound at frequencies that are used for US-BBBD [95]. Three extracranial ultrasound systems and one implantable ultrasound system are currently in clinical development (Fig. 3).

The ExAblate® system, developed by InSightec (InSightec, Tirat Carmel, Israel), is an extracranial device that has been approved for thermal ablation in the

Obstacles to overcome for wide clinical adoption of US-BBBD

Many preclinical studies have shown that US-BBBD may allow tumor control and increased survival in different murine models of brain tumors. However, tumor responses were varied [76,77]. The vascularization of the tumor, pharmacochemical characteristics of the drug used, ultrasound parameters, and other factors all influence the efficacy of this approach. Although a trend for tumor control and a better OS and PFS has been observed in the SonoCloud-1 clinical trial [99], no significant increases

Conclusions

US-BBBD with LIPU has been investigated in numerous preclinical studies and has recently entered clinical trials with encouraging results. The technique allows for safe, repeatable, and targeted opening of the BBB and increased uptake of therapeutic agents into the brain parenchyma and brain tumors. The range of drugs used in preclinical studies shows the potential of this approach. These preliminary results will have to be confirmed in larger clinical trials for this technique to gain further

Funding sources

Kevin Beccaria's research is supported partly by a grant from Cure Starts Now and the DIPG Collaborative. Jacques Grill's research is supported partly by the Charity Etoile de Martin.

Declaration of competing interest

M. Canney and Guillaume Bouchoux are employees of CarThera. A. Carpentier is a paid consultant to CarThera. K. Beccaria has previously been employed by CarThera. A. Carpentier, K. Beccaria, and M. Canney, and G. Bouchoux are inventors on intellectual property related to the SonoCloud® device that has been licensed to CarThera. A. Carpentier and M. Canney have ownership interest in CarThera.

Acknowledgements

The authors acknowledge graphic designer Quentin Beccaria for his help in creating Fig. 1, Fig. 3, as well as David M. Wildrick, Ph.D. for assistance with editing.

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