Biomaterial Scaffolds as a Platform for Focal Therapy Against Disseminated Cancer Cells

Abstract

The primary cause of death for cancer patients stems not from the primary tumor, but from the spread of the disease to distal sites. Once the cancer has become detectable past the point of origin, tumor burden in vital organs is typically too high, limiting the efficacy of current treatment options. Development of novel therapies to target disseminated cancer cells prior to the onset of extensive metastatic burden could improve patient outcomes. Focal therapy, or energy-based ablation, has been successfully used to treat solid tumors, but has yet to be effectively applied toward disseminated cells. Microporous polymer scaffolds have previously been developed to capture metastatic breast cancer cells in vivo, and have been shown to reduce tumor burden in vital organs and improve survival. The purpose of this dissertation is to further improve the therapeutic potential of these biomaterials by destroying recruited cancer cells. Chapter 1 discusses in further detail how these scaffolds recruit metastatic cancer cells and how different types of focal therapy have been used to treat solid tumors in the clinic. To demonstrate that focal therapy could be used to kill cells within the scaffold, metal disks were integrated into polymer scaffolds to serve as a heat source through induction heating for focal hyperthermia. It was shown in Chapter 2 that these modified scaffolds could be applied successfully to kill infiltrating cells in vivo. The release of cancer-specific antigens following ablation of metastatic cells could be utilized to induce an anti-cancer systemic immune response. Utilizing melanocytes because of their well-defined tumorigenic antigens, collaborative work demonstrated that lysates generated from ablation via irreversible electroporation (IRE) resulted in the greatest amount of T cell activation in vitro in comparison to focal hyperthermia or cryogenic ablation. Thus, for potential future combinatorial applications with immunotherapy, Chapter 3 investigated methods to introduce IRE to polymer scaffolds to treat disseminated cells. To accomplish this, metal mesh electrodes were integrated on either side of polymer scaffolds to create a near-uniform electric field distribution. These modified scaffolds were shown to be capable of complete ablation of infiltrating cells upon IRE in vivo in some mice, although further refinement is required to eliminate the variability in the response. The amount of antigen release from the treatment of recruited cells may be insufficient to induce a robust immune response following IRE treatment, and the local delivery of adjuvants may be required. Chapter 4 explored how polymer scaffolds could be coupled with inducible release of small molecules after electroporation. Scaffolds were modified to facilitate conjugation of inducible drug carriers and properties affecting IRE-mediated release were investigated to identify optimal conditions. In Chapter 5, polymer scaffolds were evaluated for recruitment of melanoma cells in both experimental and spontaneous metastasis models such that future studies of the application of combined focal and immunotherapy to disseminating tumor cells via biomaterial scaffolds could be performed in mouse models in which defined antigens could be used to track the efficacy of treatment. Finally, recommendations for future studies were discussed in Chapter 6. Altogether, the results of these studies represent an advance in the development of treatments that can target metastatic cancer, for which there are currently few effective therapeutic options.