BME PhD Dissertation Defense - Eric Bressler
- Starts: 2:00 pm on Friday, March 17, 2023
Title: “Engineering Biomaterial-Enhanced Therapeutics to Control Locally Aggressive Malignancies”
Advisory Committee: Mo Khalil, PhD – BU BME (Chair) Mark Grinstaff, PhD – BU BME (Co-Advisor) Wilson Wong, PhD – BU BME (Co-Advisor) Yolonda Colson, MD/PhD – MGH Division of Thoracic Surgery Gerald Denis, PhD – BU Pharmacology and Experimental Therapeutics
Abstract: At least 10% of all cancer deaths are attributable to local tumor disease burden. In select cases, existing treatments such as surgery, chemotherapy, radiation, and immunotherapy demonstrate efficacy in halting or slowing cancer progression to improve survival. However, these strategies remain insufficient for many patients, resulting in locoregional spread, locoregional recurrence, or progression to metastatic disease while also inducing dose-limiting toxicity. Biomaterials enable localized delivery of small molecules and proteins to improve safety and efficacy of cancer therapies. To leverage the safety and efficacy of biomaterials for local cancer treatment, we developed electrospun, hydrophobic nanofiber meshes that deliver small molecules and proteins. The meshes are biodegradable, biocompatible, and mechanically robust, making them ideal delivery vehicles for intraoperative care in the context of local tumor resection. We optimized the meshes to deliver the chemotherapeutic doxorubicin via drug encapsulation within the nanofibers and within hydrophobic coatings made of poly(glycerol mono-stearate-co-caprolactone) (PGC-C18). The meshes prevent local sarcoma recurrence while avoiding cardiotoxicity associated with systemic doxorubicin therapy. We next utilized this mesh formulation to encapsulate grazoprevir (GZV), an FDA approved drug recently repurposed as an inducer molecule for a logic chimeric antigen receptor (CAR) T cell. Using the meshes, we can modulate release over time and control cytokine expression in vitro. Finally, we designed meshes that adsorb proteins and release them in a tunable manner through wetting modulation, named ZipCAR Adaptor Modulation using a BiOdegradable Nanofiber Implant (ZAMBONI). We used ZAMBONI to deliver universal CAR T cell adaptor proteins, which connect CAR T cells to cancer cells in a modular fashion. We demonstrate improved safety and efficacy in models of ovarian carcinoma and mesothelioma without evidence of on-target, off-tumor toxicity, a common mechanism of CAR T cell toxicity. Together, these results demonstrate a novel and robust approach to improve safety and efficacy in local cancer therapy.
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