Translational Combinations of Nanocarriers and Blockers for Metastatic Breast Cancer

ABSTRACT Metastasis contributes to the vast majority of breast cancer deaths but current therapies for disseminated disease have limited efficacy and significant side effects. Immune checkpoint blockade (ICB) therapy has outstanding promise for breast cancer in late stages but is currently only approved for triple-negative cancers (TNBC) that stain positive for PD-L1 protein; of these patients, only ~25% show an initial response. Although the cause of divergent response is multifactorial, it is believed that “re-educating” immunosuppressive immune populations within tumors will increase the response rate. However, approaches to modulate cells are primarily based on systemically administered immunostimulatory drugs which have severe side effects. This project will develop a targeted therapy that delivers immunostimulatory drugs to immunosuppressive macrophages in metastatic breast tumors while minimizing effects in off-target tissues. With most macromolecular delivery strategies, the vast majority of an intravenously administered dose accumulates in the liver and spleen. We discovered that for certain nanocarriers, liver and spleen uptake can be blocked with adjuvants so that the nanocarriers accumulate in macrophages of orthotopic TNBC tumors in mouse models. We determined that this strategy could be used to deliver a compound that reduced tumor burden in combination with ICB therapy. The free drug alone is potently immune-stimulating but is too toxic for systemic treatment in humans. Remarkably, the nanocarrier and blocker combination reduces serum cytokine release 37-fold relative to the free drug. The nanocarriers and blockers are composed of highly biocompatible materials that are in routine clinical use. This project will optimize the composition of these agents for biodegradation and elimination to maximize the potential for clinical translation and further optimize the dosing and scheduling for delivery in combination with ICB therapy. At the conclusion of this project, we will have designed an optimal approach to deliver immune modulators selectively to metastatic cancerous tissue, and macrophages within that tissue, to maximize efficacy while minimizing side effects. This strategy has the potential to revolutionize cancer therapy, similar to how nab-paclitaxel (Abraxane) has improved breast cancer outcomes through targeted therapy.