Integrated time nanosecond pulse irreversible electroporation (INSPIRE) is a minimally invasive treatment for inoperable solid tumors developed by the PI. This treatment uses ultrashort electrical pulses to destabilize the cell membrane and induce a tunable combination of necrotic and apoptotic cell death within a well-defined volume. The therapy is implemented by introducing one or more electrodes into the tumor then delivering a series of 500ns to 2000ns electrical pulses between an electrode and an external grounding pad. To enable treatment of tumors which occur near our around critical structures active temperature feedback is utilized to limit Joule heating and prevent deleterious thermal injury. We have validated the efficacy of INSPIRE treatments utilizing in vitro 3D tumor models, against murine tumors, in healthy liver parenchyma in vivo, and in a pre-clinical safety/efficacy trial in veterinary patients. Using a combination of ex vivo, in vivo, and computational results we hypothesize that INSPIRE will be a safe and effective treatment for the vast majority of liver tumors utilizing a single applicator approach and a compatible pulse generator capable of 1,000 to 10,000V outputs when active temperature control is utilized to prevent off-target thermal injury. This hypothesis will be tested through a combination of ex vivo validation and in vivo safety and efficacy studies in the proposed work.

An estimated 42,000 patients are diagnosed with primary liver cancer per year with an even larger number of patients will developing liver metastasis. Unfortunately, the vast majority of these patients are not candidates for surgical resection, which is the only reliably curative treatment for liver tumors, yielding a five year survival rate of approximately 15%. The clinical challenge is that most tumors form deep within the organ, near major blood vessels, bile ducts, or nerves which complicate surgical removal. Algorithmically Controlled Electrotherapy (ACE) is a new minimally invasive technique developed by the PI for the treatment of inoperable tumors. This treatment uses brief electrical pulses to destabilize the cell membrane and induce a tunable combination of necrotic and apoptotic cell death. In this proposal we will collaborate with industrial partners to develop a new pulse generation topology to enable the transition of ACE treatments to the clinic. Automated temperature control algorithms will be utilized to deliver energy through the ideal combination of applicators to minimize treatment times while preventing deleterious thermal injury to critical structures adjacent to the tumor under treatment. The new instrumentation and software will be validated in large animal models and clinical veterinary patients.

An estimated 42,000 patients are diagnosed with primary liver cancer per year with an even larger number of patients will developing liver metastasis. Unfortunately, the vast majority of these patients are not candidates for surgical resection2, which is the only reliably curative treatment for liver tumors, yielding a five year survival rate of approximately 15%. The clinical challenge is that most tumors form deep within the organ, near major blood vessels, bile ducts, or nerves which complicate surgical removal. Phased Algorithmically Controlled Electrotherapy (PACE) is a new minimally invasive technique developed by the PI for the treatment of inoperable tumors. This treatment uses brief electrical pulses to destabilize the cell membrane and induce a tunable combination of necrotic and apoptotic cell death. In this proposal we will develop a new pulse generation topology to enable the scaling up of PACE treatments from in vitro models to pre-clinical large animal models. This topology will be capable of delivering energy through four synchronous electrodes to enable treatments to be administered to the vast majority of tumors encountered clinically. Automated temperature control algorithms will be utilized to deliver energy through the ideal combination of applicators to minimize treatment times while preventing deleterious thermal injury to critical structures adjacent to the tumor under treatment. The new instrumentation and software will be validated in a perfused ex vivo liver model.

Over 260,000 new cases of breast cancer that are diagnosed annually in the United States. While surgical lumpectomy and mastectomy are the clinical curative gold standards, these treatments are generally not effective against disease which has become metastatic. INSPIRE is a new cancer therapy developed at NCSU which uses nanosecond duration electrical pulses to destroy tumors in place without the need for chemotherapy INSPIRE therapy uniquely enables clinicians to deliver treatments which have an increased potential of inducing a positive immune response against locally advanced and metastatic disease. Proof of concept validation of this technology has been demonstrated in laboratory models of liver cancer. In the proposed project, we will investigate a new clinical target, breast cancer, which will expand the potential patient population and increase the value of intellectual property associated with this technology. The efficacy of INSPIRE therapy for the treatment of breast cancer will be evaluated in a clinically relevant model of client owned canine patients with spontaneous disease which will enable rapid clinical translation of techniques and protocols developed.

Intradermal nanosecond pulse induced reversible electroporation (INSPIRE) is a novel technology developed to enhance delivery of COVID DNA vaccines under development. This technique minimizing pain, muscle stimulation, and off target lethality associated with existing technologies. Here, we will optimize INSPIRE protocols to enable a rapid transition to in-vivo trials.

INSPIRE is a new cancer therapy which uses ultrashort high intensity pulsed electric fields to treat inoperable tumors. A unique feature of this technique is that cell death can be tuned to favor apoptotic or necrotic pathways in the absence of extreme temperatures which may denature critical antigens necessary for stimulating a systemic immune response. This technique has previously been demonstrated to be effective at inhibiting tumor growth in immune suppressed murine models and is currently under evaluation in large animal models of melanoma. We hypothesize that INSPIRE treatment can be tuned to optimize the release of tumor antigens and in combination with monoclonal antibodies produce a systemic immune response. This proposal will optimize INSPIRE therapy for murine melanoma in a 3D tumor model and evaluate the effect of these optimized protocols against primary and metastatic disease in an immune competent murine model. The ultimate goal is to develop protocols which result in a vaccine like response to treatments of a primary tumor resulting in systemic immunity against metastatic disease.