Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

Lee, Hohyun; Guo, Yutong; Schoen, Scott; Degertekin, F. Levent; Arvanitis, Costas D.

doi:10.1126/sciadv.add2288

Cited by 28 publications

(17 citation statements)

References 75 publications

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“…UMBO was optimized to disturb one hemisphere; however, in our PK analysis, we used a whole-brain homogenization method; therefore, local concentrations of nivolumab could have been higher. Consistent with our data, a study has shown that UMBO enhanced the delivery of bevacizumab 32 ~149 KDa and anti-PD1 33 compared to non-sonicated brain in a glioma mouse model. UMBO plus 200 µg of the anti-PD-L1 biweekly treatment regimen was used to maintain the higher concentration of anti-PD-L1 within the brain parenchyma.…”

Section: Discussionsupporting

confidence: 92%

Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Ahmed¹,

Quissac²,

Lemaire³

et al. 2022

Preprint

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Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A Blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10µl/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

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Section: Discussionsupporting

confidence: 92%

Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Ahmed¹,

Quissac²,

Lemaire³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…UMBO was optimized to disturb one hemisphere; however, in our PK analysis, we used a whole-brain homogenization method; therefore, local concentrations of nivolumab could have been higher. Consistent with our data, a study has shown that UMBO enhanced the delivery of bevacizumab [ 31 ] ~149 KDa and anti-PD1 [ 32 ] compared to non-sonicated brains in a glioma mouse model. UMBO plus 200 µg of the anti-PD-L1 biweekly treatment regimen was used to maintain the higher concentration of anti-PD-L1 within the brain parenchyma.…”

Section: Discussionsupporting

confidence: 92%

Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model

et al. 2023

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Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood–brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A blood–brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10 µL/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly opened the BBB. BBB opening was confirmed visually and microscopically using Evans blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice’s survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome in order to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

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“…They found that FUS did not alter the frequency of CD8 + T Cells across evaluated organs significantly, but upregulated checkpoint molecules (PD-1 and TIM-3) on these cells were detected at 1-week post-FUS, suggesting the increased activation of the T Cells. Similarly, the study of Lee et al indicated that a closed-loop controlled MB-FUS system could lead to a better penetration and distribution of the anti-PD1 antibody in the GL261 glioma mouse model ( Lee H. et al, 2022 ). Their proposed delivery system increased the interaction of proinflammatory macrophages within the PD-1-expressing TME without promoting global inflammation in non-tumor tissue.…”

Section: Fus-mediated Delivery Systems Enhance the Efficacy Of Icb Fo...mentioning

confidence: 98%

“…Advances in delivery technologies, in particular, could improve the curative potential of ICB and could also reduce ICB-related toxicities ( Kubli et al, 2021 ). Multiple delivery modes, including photons ( Cheng H. et al, 2022 ; Chen et al, 2022 ), ultrasound ( Lee H. et al, 2022 ), alternating magnetic fields ( Ge et al, 2023 ), and radiofrequencies ( Shou et al, 2022 ), can increase the accumulation of small-molecule drugs within the TME, enable more efficient and precise targeting of the specific tumor and/or immune cells, re-shape the TME and reduce off-target adverse effects ( Izci et al, 2021 ). Therefore, combining ICB with various delivery platforms has been one of the promising strategies to improve ICB for solid tumors ( Gong et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors

Xia

Xiong

et al. 2023

Front. Pharmacol.

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In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in “cold tumors” with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

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Spatially targeted brain cancer immunotherapy with closed-loop controlled focused ultrasound and immune checkpoint blockade

Cited by 28 publications

References 75 publications

Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors

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