Targeting RNA Sensing to Enhance Immunotherapy Responses in Kidney Cancer
Abstract
Despite important advances in therapy and detection over the past decade, the survival rate for metastatic kidney cancer remains unacceptably low. Indeed, this year alone over 14,000 people in the United States will die from this disease, including military personnel and Veterans, who are at higher risk of kidney cancer. Cancer immunotherapy seeks to harness 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 kidney cancers; T cells have the ability to 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. Checkpoint inhibitors are transforming the treatment of a growing number of cancers, including kidney cancers, with some patients exhibiting truly remarkable outcomes. However, the vast majority of kidney cancer patients do not respond completely to this type of immunotherapy because the T cells that enter tumors are dysfunctional and cannot be properly reactivated by checkpoint inhibitors. The goal of this research is to develop a safe and effective immune-based therapy for renal cell carcinoma (RCC) by activating the immune system to increase the number and tumor-killing ability of T cells. By doing so, this research directly addresses the FY21 KCRP Focus Area of Developing novel therapeutic strategies for the treatment of kidney cancer, such as novel drug targets, therapeutic modalities and agents, treatment combinations and drug delivery systems. 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, we have found that some PRRs also play an important role in the immune system s natural ability to generate T cells that can eradicate kidney cancers. One such PRR is RIG-I, which is used by cells to recognize certain viruses (e.g., the flu virus). Our preliminary studies show that activation of RIG-I, using a molecule that safely mimics a viral infection, can inhibit tumor growth in a mouse model of kidney cancer. This type of molecule has already been in clinical trials, but until our recent studies had not previously been explored in kidney cancer. The molecule also has not yet been optimized for maximum effectiveness. For our findings to have maximal clinical impact, the molecule that activates RIG-I, called 3pRNA, must be delivered to tumors safely and effectively. To address this challenge, our team is developing lipid nanoparticles (LNPs) that dramatically enhance the activity and therapeutic potency of 3pRNA. These LNPs are very similar to those already in clinically approved medicines, including the recently approved mRNA COVID-19 vaccines, but they must be further optimized for 3pRNA and for kidney cancer immunotherapy. Therefore, the first part of our proposal focuses on optimizing the LNP technology to more specifically target kidney tumors, which we expect will increase efficacy and safety. The second part of our proposal seeks to understand how RIG-I activation is able to galvanize the immune system to recognize and eliminate kidney cancers. These are fundamental studies that will be important to the clinical development of our therapeutic and to understanding how to best combine our therapy with other drugs. The final part of our project will define how RIG-I activation can synergize with currently approved immune checkpoint inhibitors to improve therapeutic responses in multiple mouse models of kidney cancer. We are pursuing these directions with an eye toward rapid clinical translati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210661
Entities
People
- John T Wilson
Organizations
- United States Army
- Vanderbilt University