Engineering RIG-I Agonists to Enhance Immunotherapy in Metastatic Breast Cancer
Abstract
The 5-year survival rate for stage IV, metastatic breast cancer remains unacceptably low at under 25%, and unfortunately therapies that can eliminate metastatic disease still remain elusive. Cancer immunotherapy seeks to harnesses a patient’s own immune system to specifically destroy cancer cells throughout the body with minimal toxicity to surrounding tissue, while also training the immune system to “remember” how to kill cancer cells if they return years later. The immune system plays a key role in fighting breast cancer; T cells have the ability find and destroy malignant cells, but tumors are able to disarm T cells that migrate into the tumor. Checkpoint inhibitors are a type of immunotherapy that works by reactivating these T cells, allowing them to complete their mission of destroying cancer cells. This has transformed the treatment of a growing number of cancer types with some patients exhibiting truly remarkable outcomes and, importantly, durable cures. A checkpoint inhibitor has recently been approved for some patients with metastatic triple-negative breast cancer (mTNBC), generating excitement about the potential of immunotherapy for breast cancer. However, the vast majority of breast cancer patients do not respond to checkpoint inhibitors because their tumors are considered “cold” in that they lack a sufficient number of infiltrating T cells that can be reactivated. The goal of this research is to develop a safe and effective immune-based therapy for metastatic breast cancer that “jump-starts” the immune system to increase the number and tumor killing ability of T cells – a novel therapy for turning “cold” tumors “hot.” By doing so, this research 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. Our innate immune system plays a critical role in protecting us against infections and uses specialized molecules called pattern recognition receptors (PRRs) to “sound the alarm” in response to pathogen invasion. Interestingly, recent work has shown that some PRRs also play an important role in immune system’s natural ability to generate T cells that can eradicate tumors. One such PRR is RIG-I, which is used by cells to recognize certain viruses (e.g., flu virus). Our recent work has shown that activation of RIG-I, using a molecule that safely mimics a viral infection, can inhibit breast tumor growth by stimulating T cells to migrate into metastatic tumors and destroy breast cancer cells. This type of molecule is already in clinical trials, but until our recent studies had not previously been explored in breast cancer. The molecule also has not yet been optimized for maximum effectiveness. Therefore, for our findings to have maximal clinical impact, the molecule that activates RIG-I, called 3pRNA, must be delivered to tumors safely and effectively. Our team has engineered novel “smart” nanoparticles (NPs) that dramatically enhance the activity and therapeutic potency of 3pRNA. The first part of our proposal focuses on optimizing this technology for delivering 3pRNA to metastatic breast tumors. In the second part of our proposal, we will develop 3pRNA “pro-drug” molecules that are delivered in an inactive form, but then become activated only in response to specific factors expressed within breast tumors. This approach maximizes the safety of this promising new drug. We hypothesize that combining NPs with 3pRNA pro-drugs will trigger a localized inflammatory response that “reprograms” breast tumors to generate anti-tumor T cells that inhibit tumor growth. Our exciting initial findings support this hypothesis and motivate further development of this innovative immunotherapeutic technology for treating metastatic breast cancer. Additionally, our studies will focus on evaluating rationally designed drug
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010624
Entities
People
- John T Wilson
Organizations
- United States Army
- Vanderbilt University