Inside-Out Immunotherapy: Combating Neuroblastoma via Nanoparticle-Directed Reprogramming of the Tumor Microenvironment
Approximately 50% of children with neuroblastoma have an aggressive and high-risk form of the disease. Despite intensive surgery, chemotherapy, and radiation, the survival rate for these patients is unacceptably low (<40%). This need for fundamentally new approaches to combat NB motivates the objectives of this project.
The immune system has an intrinsic ability to find and destroy cancer cells. But neuroblastoma tumors have developed mechanisms protect themselves against this assault by creating a local "microenvironment" that suppresses the tumor killing capacity of the immune system.
The goal of this project is to develop and evaluate a new class of therapeutic that "retrains" the immune system to eliminate neuroblastoma and prevent its recurrence. To accomplish this, we will develop a simple and safe material that can be injected directly into neuroblastoma tumors that cannot be completely removed by surgery. We will engineer this material to sustain the release of a single therapeutic agent that we have designed to target two molecules that regulate immune responses. The first, PD-L1, suppresses the tumor killing ability of immune cells in the tumor, and so we will inhibit PD-L1. The second, RIG-I, helps the immune system kill tumor cells, and so we will activate this pathway. This process will "re-awaken" the immune cells within the tumor, allowing them to kill surrounding cancer cells, while also turning the tumor site "inside-out" by activating immune cells that can search for and destroy neuroblastoma cells throughout the body and "remember" how to kill these cells if they return.
“I very am honored and excited to have received this award from ALSF. My lab
works at the intersection of engineering and immunology, and we are interested
in innovating new technologies for modulating and understanding the immune
system. This support from ALSF provides an amazing opportunity for our group
to tackle challenges in pediatric cancer from this unique perspective, and will
jump-start our work in developing new therapeutics and drug delivery strategies
for neuroblastoma immunotherapy. I am also excited about the interdisciplinary
collaborations and relationships that this award will help foster, which I think will
inspire creative new ideas that get us closer to finding cures for childhood
cancers.” - John Wilson