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BACKGROUND The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas. Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. Here we investigate the pharmacokinetics and safety of this approach of repeated delivery of albumin-bound paclitaxel (Abraxane®, ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection. METHODS A Phase 1 dose-escalation trial using Bayesian adaptive design was conducted (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and adequate bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection allowed for investigation tissue concentrations and pharmacokinetics. RESULTS Seventeen patients have been treated at six escalating ABX dose levels (40-260 mg/m2). At dose of 260 mg/m2, a grade 3 reversible taxane-associated dose limiting encephalopathy was observed in one patient. The patient continued treatment at a lower dose in subsequent cycles. A second patient exhibited encephalopathy on cycle 2. One patient developed grade 2 cumulative peripheral neuropathy. Intraoperative pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased 3.7-fold after LIPU/MB. sc-RNA-sequencing showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis as well as cell-cell and cell-matrix adhesion. CONCLUSIONS The LIPU/MB using skull-implantable ultrasound enhances the penetration of ABX in large regions of the brain. The procedure can be performed repeatedly and safely. LIPU-based BBB opening leads to transcriptional alterations in brain endothelium. Funding: NIH/NCI 1R01CA245969-01A1, CarThera (SC9 devices), BMS/Celgene (Abraxane®).

Cancer immunoediting shapes tumor progression by the immunological selection of tumor cell variants that can evade immune recognition. Given the immune evasive cellular diversity of glioblastoma, we hypothesized that CD8+ T-cells mediate immunoediting in this tumor. We evaluated tumor progression in the absence of CD8+ T-cells by depleting this immune cell population in a transgenic murine glioma model. Tumors generated in the absence of CD8+ T-cells developed poorly in recipients with intact immunity, implying a more immunogenic profile. These tumors demonstrated increased chromosomal instability, gene fusions, MAPK signaling, and macrophage infiltration. These observations were stochastic, suggesting variability in the mode of tumor evolution in the absence of this immune effector. MAPK activation was correlated with macrophage recruitment in two transgenic murine models and the human disease. Our results indicate that CD8+ T-cells mediate a strong immunoediting selection in glioblastoma that protect against the hallmarks of cancer and drive immune evasion.