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.