Synergistic blood-brain barrier indoximod delivery and selective treatment of malignant glioma using Pulsed Field Ablation

About This Grant

Abstract H-FIRE is an emerging, minimally invasive focal ablation technique that utilizes low energy, microsecond-long electric pulses delivered locally within targeted tissues for several minutes. Tumor cell death is rapidly induced through a loss of cellular homeostasis and is not dependent on thermal effects. Due to its non-thermal mechanism, H-FIRE has been shown to preserve important tissue components such as the extracellular matrix, blood vessels, and nerves, as well as the immunogenicity of tumor antigens compared to other ablation modalities. H-FIRE can ablate predictable volumes of tissue without the need for neuroparalytics as is required for its FDA-approved predecessor, and safe and effective H-FIRE treatment has been demonstrated in rat glioma models and canine patients with spontaneous brain tumors. Key advantages of H-FIRE for GBM treatment include i) glioma and glioma stem-like cell specific ablation resulting from tuned H-FIRE pulses; ii) enhancement of ablation through combination with a targeted molecular adjuvant; iii) reversible BBB breakdown and enhanced delivery of molecular therapeutics from the dissipating H-FIRE field well beyond the tumor margin; iv) electrical feedback for monitoring and modeling treatment; and v) activation of innate and adaptive anti-tumor immune responses from intracranial H-FIRE. These advantages motivate the central hypothesis for this effort, specifically that H-FIRE combined with the cancer adjuvant immunomodulatory drug, indoximod, will overcome key drivers of therapy resistance by combining effective ablation of a core tumor mass with enhancing delivery and efficacy of a small molecule drug that is normally blocked from entry by the BBB. The project has two aims. In Aim 1, pulse parameters will be evaluated on their ability to completely and selectively ablate malignant tissue in comparison to normal brain tissue, to corroborate preliminary in vitro data using a more relevant in vivo glioma rat model. In Aim 2, the in vivo synergy resulting from the combination of H-FIRE with indoximod will be quantified using an orthotopic rat GBM model. Computational models and in vitro experimentation are highly adaptable, allowing real-time data collection and analysis. However, fully replicating the intricate brain environment and the complete surgical procedure involving the skull can only be accurately assessed using an in vivo animal model. In selecting the species and strain, female and male Fischer rats were chosen because no lower species model is available that uniquely support the electrode configuration for in vivo brain electroporation studies. A mammal is needed for adequate analysis of tissue ablation. Additionally, species matching will allow us to make comparisons to previously completed studies. These aims will lead to independently optimized H-FIRE protocols for i) ablation of a tumor bulk resulting in effective anti-tumor immune stimulation and ii) reduction of barriers to the efficacy of indoximod adjuvant therapy. Intraoperative MRI-guided electrode insertion will allow for highprecision electrosurgery and fine-tuned BBB disruption and brain cancer treatment efficacy in preparation for treating canine patients, with the expectation to translate those results to human patients