Combinatorial Pulsed Field Alation for the Treatment of Solid Tumors

About This Grant

Project Abstract Many solid cancers are inoperable due to either tumor size or because the tumor is attached to, or near, major blood vessels, vital organs or other critical tissues. Focal ablation modalities utilizing a variety of energy forms to destroy/debulk tumor tissues are frequently used in the management of inoperable solid cancers. More than 45,000 tumor ablation procedures are performed each year. Three thermal ablation techniques, radiofrequency ablation (RFA), cryoablation (CA) and microwave ablation (MWA), account for more than 80% of all procedures, but residual tumor deposits often lead to recurrence rates that are 2 to 10 times higher than recurrence rates following surgical resection. As a result, patients with inoperable tumors have worse survival outcomes compared to patients with resectable tumors. Integrated Nanosecond Pulse Irreversible Electroporation (INSPIRE) is a novel, minimally invasive solid tumor ablation modality. This thermally-regulated approach uses ultrashort alternating polarity electrical pulses to destabilize tumor cell membranes while preserving the integrity of nearby vital structures. A key advantage of INSPIRE, which forms the crux of this proposal is the flexibility in energy delivery and numerous parameters combinations that allows us to modulate cell death mechanisms to favor immunogenic pathways, and subsequent antitumor immune responses. Induction of robust antitumor immunity following focal ablation is crucial for eliminating residual tumor cells and preventing local or distant recurrence which can be enhanced with secondary immunotherapy agents such as checkpoint inhibitors. Based on our preliminary studies, we hypothesize that there is a ‘best’ or most immunogenic INSPIRE protocol which maximizes the resultant antitumor immune. We further hypothesize that an adjunctive immunotherapy can boost the INSPIRE-induced antitumor response, thus enhancing both local and systemic tumor control. These hypotheses will be tested in an aggressive, transplantable murine melanoma model before translation into comparative oncology trials in pet dogs with spontaneous melanomas via three aims: Aim 1: Develop and validate INSPIRE protocols to maximize tumor-specific immunity; Aim 2: Evaluate the timing of adjunctive immunotherapy relative to INSPIRE; Aim 3: Validation of Combinatorial INSPIRE in a Spontaneous Large Animal Model of Disease. These aims will determine the treatment parameters which maximize immune stimulation via INSPIRE, improve systemic anti- tumor immune responses via optimized adjunctive immunotherapy regimens, and demonstrate clinical superiority of this combined approach in a relevant large animal model. Our long term goal is to develop a novel, minimally invasive focal treatment paradigm that is capable of preventing recurrences and eliminating metastatic deposits. Successful completion of the proposed project will support further translation of INSPIRE plus adjunctive immunotherapy into human trials while providing a state-of-the-art treatment for thousands of companion animals per year.