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Focused Ultrasound for Blood-Brain Barrier Opening and Delivery of Anti-PD1 in Diffuse Midline Gliomas.
PURPOSE/OBJECTIVE(S): Diffuse midline glioma with H3K27 mutation is a fatal pediatric brain tumor, most commonly arising in the brainstem. This tumor remains universally fatal, despite a multitude of clinical trials, with a median overall survival of only 9-12 months. While immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors, delivery past the blood brain barrier (BBB) remains challenging. Programmed cell death protein 1 (PD1) is an immune checkpoint protein expressed on the surface of activated T cells; interaction with its ligand, PDL1, is tumor-protective, dampening T cell response. Recent phase I clinical trials have shown that ICIs targeting proteins along the PD1/PDL1 axis are well tolerated in patients with DMG; however, efficacy remains low. The blood-brain barrier (BBB) poses a major challenge to the efficacious delivery of therapeutic agents with large molecular size, such as anti-PD1. We hypothesize that BBB opening (BBBO) using focused ultrasound (FUS), a form of non-ionizing acoustic radiation, can enhance delivery and efficacy of anti-PD1 for treatment of DMG.
MATERIALS/METHODS: We established a syngeneic mouse DMG model with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). Magnetic resonance imaging (MRI) was utilized to evaluate BBBO and tumor progression. We measured delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1.
RESULTS: We demonstrate that delivery of anti-PD1 can be enhanced over 3.5-fold after reversible BBBO with FUS and concurrent microbubble administration. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrate that combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival.
CONCLUSION: Our results support that FUS-mediated BBBO can increase treatment efficacy of anti-PD1 in a DMG murine model, due to improved targeted delivery to the tumoral region after systemic antibody administration. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.
MATERIALS/METHODS: We established a syngeneic mouse DMG model with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). Magnetic resonance imaging (MRI) was utilized to evaluate BBBO and tumor progression. We measured delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1.
RESULTS: We demonstrate that delivery of anti-PD1 can be enhanced over 3.5-fold after reversible BBBO with FUS and concurrent microbubble administration. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrate that combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival.
CONCLUSION: Our results support that FUS-mediated BBBO can increase treatment efficacy of anti-PD1 in a DMG murine model, due to improved targeted delivery to the tumoral region after systemic antibody administration. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.
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