Inside-Out Immunotherapy: Preventing Metastatic Breast Cancer Recurrence via Nanoparticle-Directed Modulation of the Tumor Microenvironment
Abstract
Increased public awareness and improved breast cancer screening have resulted in a dramatic increase in the early diagnosis of breast cancer, and 92% of breast cancers (>210,000 women this year in the United States) are now detected at an early stage. However, an estimated 20%-30% of these women will experience a recurrence within 10 years. Breast cancer is particularly lethal when it recurs. Of the 40,000 breast cancer deaths in the United States this year, approximately 90% will be a consequence of metastatic disease, most commonly a recurrence. Therefore, for the majority of women diagnosed with breast cancer, metastatic recurrence is the major barrier to long-term survival. By harnessing the intrinsic ability of a patient s immune system to eliminate cancerous cells, this proposal directly addresses the Overarching Challenges of (1) eliminating the mortality associated with metastatic breast cancer and (2) revolutionizing treatment regimens by replacing drugs that have life-threatening toxicities with safe, effective interventions. The immune system plays a key role in fighting breast cancer; immune cells, referred to as leukocytes, have the ability find and destroy malignant cells. But many cancers have developed mechanisms to escape immune detection and can even highjack the immune system to empower tumor growth. This is the case in breast cancer, where the local environment around the tumor (the tumor "microenvironment," or TME) is rich with cells and molecules that suppress the immune system s ability to kill breast cancer cells. The immune-suppressive TME is clearly linked to breast cancer recurrence and metastasis, correlates negatively with disease-free survival, and has been the major barrier to the success of many previous attempts to educate the immune system to fight cancer. Our goal is to reverse this environment from one that suppresses the immune system s ability to kill breast cancer cells to one that supports it. By doing so, we will be able to reprogram the immune system to recognize and eliminate residual and/or drug-resistant cancer cells that are the seeds for metastasis and recurrence. To reprogram the TME, we are targeting two molecules. The first, TGF-beta, is enriched in the TME and suppresses the ability of leukocytes in the tumor to kill cancer cells. We will inhibit TGF-beta signaling in cancer cells and tumor leukocytes. The second, RIG-I, is used by all cells to recognize viruses, but this pathway can also be exploited to activate leukocytes to kill tumor cells. We will activate RIG-I signaling in cancer cells and tumor leukocytes. Importantly, we will achieve this using a single therapeutic agent capable of TGF-beta inhibition and RIG-I activation. To be successful, the agent must be delivered to the tumors and the TME safely and effectively. Therefore, we have designed "smart" nanoparticles for delivery into the TME. These smart nanoparticles allow the drug to reach the desired targets within cells that engulf it. Because certain tumor leukocytes are particularly adept at engulfing materials from the surroundings, the majority of the smart nanoparticles will be engulfed by local tumor leukocytes, preventing delivery to the healthy cells throughout the body. An added layer of engineering can fine-tune the sustained release of the smart nanoparticles for effective long-term delivery of nanoparticles for up to 3 weeks after a single injection. Together, we have used three layers of engineering to produce a drug that can be administered locally (directly into the tumor) for sustained release of a single agent that will "re-awaken" the immune system to kill breast cancer cells in the local TME, to "search for and destroy" breast cancer cells that may have already spread to other tissues in the body, and to "remember" how to kill breast cancer cells if they return, even many years later. This approach will be associated with less toxicity and side effects than chemot
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610064
Entities
People
- Rebecca Cook
Organizations
- United States Army
- Vanderbilt University