Julio P. Arroyo
BME PhD Proposal Presentation

Date: 2025-10-02
Time: 1-3 PM 
Location / Meeting Link: UAW 2100 & Microsoft Teams: Meeting ID: 277 885 936 434 9 Passcode: nh7gW7C7

Committee Members:
Rafael V. Davalos, Ph.D. (advisor); Susan N. Thomas, Ph.D.; Aniruddh Sarkar, Ph.D.; Irving C. Allen, Ph.D.; Yong Lu, Ph.D.


Title: Powering Up The Immune System: Multiscale Approaches of Pulsed Electric Fields To Induce Immunomodulation

Abstract:
Despite decades of effort towards developing contemporary cancer treatments such as surgical resection, chemoradiation, and early detection, poor outcomes have continued to persist due to diffuse cancer infiltration, an immunosuppressive tumor microenvironment, and residual malignancy causing localized or metastatic recurrence. Targeted immunotherapies have shown promising results through harnessing a patient’s immune system for a potent systemic antitumor response for blood-relating cancers but have displayed several shortcomings when targeting solid tumors such as distribution and trafficking into the malignancy. Further, thermal ablation modalities have become an alternative for alleviating the bulk tumor mass; however, these treatments risk causing indiscriminate damage beyond the target site, leading to destruction of surrounding healthy sensitive structures such as blood vessels and nerves. New methods capable of treating the primary tumor while targeting distant metastasis are required to improve patient outcomes. Irreversible electroporation (IRE) is a non-thermal ablation modality used clinically for treating unresectable tumors, allowing for complete local tumor ablation without injuring nearby critical structures. This therapeutic intervention employs high voltage pulsed electric fields (PEFs) to form nanoscale defects that permeabilize the cell membrane, leading to homeostatic imbalance and, eventually, cell death. Secondary to bulk tumor ablation, IRE is documented to attenuate the dense tumor stroma by clearing suppressive immune populations and alleviating hypoxia. Together, this results in both increased pro-inflammatory immune infiltration and priming for a robust anti-tumor response; however, patient-to-patient variability in native immune cell recruitment between treatments can lead to eventual recurrence in cases. This daunting limitation presents the need for complimentary therapeutics and adjuvants to ameliorate this concern when implementing IRE as a primary curative tool. This dissertation aims to address this critical gap through developing and characterizing combinatorial treatments in tandem with IRE to establish comprehensive immunomodulatory therapeutic regimens. We hypothesize that the immunological outcomes of electroporation-based therapies can be enhanced via local and systemic adjuvant therapies. The initial aim focuses on the development of in vitro and in vivo immunodeficient models to evaluate tumor responses post-treatment of lethal PEFs to understand residual malignant cell proliferation, migration, and recurrence. The following aim will investigate synergistic approaches complimenting the delivery of lethal PEFs to ensure complete tumor elimination while promoting heightened pro-inflammatory responses. The final aim will explore the feasibility of patient-specific in vivo lymph node gene transfer using PEFs for the generation of readily available CAR T-cells for use in cooperation with IRE ablation therapy. By creating novel advancements in electroporation-based therapies for promoting consistently robust inflammatory responses can offer new clinically translatable avenues for therapeutic success against primary and metastatic lesions.