Reinvigorating Antitumor Immunity in Renal Cell Carcinoma with Nanoparticulate STING Agonists
Abstract
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 work 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 cancer, with some patients exhibiting remarkable outcomes. However, the vast majority of kidney cancer patients do not completely respond to this type of immunotherapy because their tumors are considered "cold," i.e., they lack a sufficient number of properly functioning T cells that can be reactivated by checkpoint blockade. 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, a novel therapy to make tumors "hot." By doing so, this research directly addresses the KCRP Areas of Emphasis focused on "Immunotherapies" and "Microenvironment." Recent studies have shown that the STING pathway plays a critical role in the immune system s natural ability to recognize and destroy tumor cells. This has recently generated significant interest in therapeutics that activate this pathway. Our group has pioneered novel STING-activating nanoparticles (STING-NPs) built using "smart" polymers that we have engineered to dramatically enhance the activity and therapeutic potency of cGAMP, a small molecule activator of the STING pathway that is naturally produced by our bodies as a strategy to fight infections, resolve cellular injury, and ward off tumor formation. We hypothesize that STING-NPs will trigger a localized inflammatory response that "reprograms" RCC tumors to generate antitumor T cells that will migrate into metastatic sites to destroy kidney cancer cells. Our initial findings support this hypothesis, and in this proposal we will focus on optimizing this innovative immunotherapeutic technology for treating RCC and preventing its recurrence. The first part of our proposal focuses on optimizing the safety and antitumor efficacy of STING-NPs and, importantly, gaining a deeper understanding of how the STING pathway influences immune responses in RCC, which has thus far not been widely explored. These studies will utilize mouse models that mimic the immunology of human RCC as well as tissue samples isolated from RCC patients in order to validate our approach in the context of human kidney cancer. The second part of our proposal will focus on developing novel and rational immunotherapy combinations for RCC using STING-NPs to increase the efficacy of two clinically advanced immunotherapeutic drugs. These studies will focus on leveraging these new combinations in mouse models of RCC to increase long-term survival, treat metastatic disease, and generate memory to prevent tumor recurrence. Successful completion of this impactful three-year project will establish a strong foundation for an innovative new approach to RCC immunotherapy while addressing critical knowledge and technological gaps that, when filled, have potential to impact patient outcomes. To help ensure this, the project brings together a multidisciplinary team with expertise in engineering, pharmaceutical sciences, immunology, cancer biology, and clinical oncology with the common goal of ultimately translating the discoveries and innovative immunotherapies resulting from this research to the clinic to improve the lives of kidney cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810391
Entities
People
- John T Wilson
Organizations
- United States Army
- Vanderbilt University