新しい超音波装置の最初の人体試験では、一時的に血液脳関門を開き、化学療法を脳に直接送達する可能性が実証されました。 この革新的な処置により、脳内の薬物濃度が 4 倍から 6 倍に大幅に増加し、数週間ごとに数か月間繰り返された 4 分間の処置の間、患者は覚醒していました。 現在、神経膠芽腫の有効な治療法はなく、この新しい超音波技術は、この壊滅的な疾患との闘いにおいて有望な発展を遂げています。
マイクロバブルを利用した新しい超音波技術は、一時的に血液脳関門を開き、ヒトの神経膠芽腫を治療します。
致命的な脳腫瘍である神経膠芽腫の治療における最大の課題の 1 つは、最も効果的な化学療法薬が血液脳関門を通過して急速に増殖する脳腫瘍に到達できないことです。
Northwestern Medicine の研究者は最近、新しい頭蓋骨埋め込み型超音波装置を利用した最初のヒト臨床試験の結果を報告しました。 この装置は血液脳関門を開き、脳の広い領域に繰り返し浸透することを可能にし、静脈内注射による化学療法の送達を可能にします。
血液脳関門を開くための 4 分間の処置は、患者が起きている状態で行われ、患者は数時間後に帰宅します。 結果は、この治療が安全で忍容性が高いことを示しており、一部の患者は最大 6 サイクルの治療を受けています。
これは、人間の脳内の化学療法の濃度に対する超音波ベースの血液脳関門の開口部の効果を正常に定量化した最初の研究です。 血液脳関門を開くと、人間の脳内の薬物濃度が約 4 倍から 6 倍に増加することが結果で示されました。
科学者は、2 つの異なる強力な化学療法薬、パクリタキセルとカルボプラチンでこの増加を観察しました。 これらの薬は、通常の状況では血液脳関門を通過しないため、これらの患者の治療には使用されません。
このビデオは、術中の BBB 開口部の動的開口部を示しています。 脳の超音波処理と静脈内マイクロバブルの投与に続いて、科学者はフルオレセインを静脈内に注射しました。この色素は通常、脳に浸透しません。 彼らは最初に動脈でフルオレセインを観察し、次にこの染料が毛細血管にあり、続いて脳静脈にあったため、脳全体が蛍光を発しました。 最終的に、数分後、血液脳関門が開いた超音波処理された脳領域にこの色素が蓄積するのが観察されました。 クレジット：[{” attribute=””>The Lancet Oncology
In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.
“This is potentially a huge advance for glioblastoma patients,” said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.
Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.
The paper was recent published in the journal The Lancet Oncology.
The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer requires their delivery to the brain.
In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.
Blood-brain barrier recloses after an hour
The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.
“There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” Sonabend said.
Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.
In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after the removal of glioblastoma tumors.
Clinical trial for patients with recurrent glioblastoma
The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial — in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique — is to investigate whether this treatment prolongs the survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.
In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.
Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy.
“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said.
Reference: “Repeated blood–brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial” by Adam M Sonabend, Andrew Gould, Christina Amidei, Rachel Ward, Karyn A Schmidt, Daniel Y Zhang, Cristal Gomez, John F Bebawy, Benjamin P Liu, Guillaume Bouchoux, Carole Desseaux, Irene B Helenowski, Rimas V Lukas, Karan Dixit, Priya Kumthekar, Víctor A Arrieta, Maciej S Lesniak, Alexandre Carpentier, Hui Zhang, Miguel Muzzio and Roger Stupp, 2 May 2023, The Lancet Oncology.
DOI: 10.1016/S1470-2045(23)00112-2
The study was funded by the National Cancer Institute.