SURG-06. ENHANCED DELIVERY OF ANTI-PD1 FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA USING FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING
Abstract Diffuse midline glioma with H3K27 mutation is a fatal central nervous system tumor, most commonly arising in the brainstem. Despite a multitude of clinical trials, prognosis remains poor with a median overall survival of 9-12 months. Immune-checkpoint inhibitors (ICIs) have transformed the...
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Veröffentlicht in: | Neuro-oncology (Charlottesville, Va.) Va.), 2023-06, Vol.25 (Supplement_1), p.i73-i73 |
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Sprache: | eng |
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Zusammenfassung: | Abstract
Diffuse midline glioma with H3K27 mutation is a fatal central nervous system tumor, most commonly arising in the brainstem. Despite a multitude of clinical trials, prognosis remains poor with a median overall survival of 9-12 months. Immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors. 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. Here we show that delivery of anti-PD1 can be enhanced over 3.5-fold using low intensity focused ultrasound (FUS) and concurrent microbubble administration to achieve reversible blood-brain barrier opening (BBBO) in a syngeneic mouse DMG model established with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). We measured this increased delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrated that this 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. 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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ISSN: | 1522-8517 1523-5866 |
DOI: | 10.1093/neuonc/noad073.282 |