Developing a Heparanase and NK Cell-Based Nanoimmunotherapy to Treat Neuroblastoma
Mentor: Dr. Rohan Fernandes
Neuroblastoma is a type of cancer that develops from early nerve cells. 90% of diagnoses are made in children under the age of 5. The five-year survival rate for children with high-risk neuroblastoma is 50%, and side effects of treatment include long-term hearing loss, developmental delays, and secondary cancers. A better treatment must be found.
The Fernandes Lab develops treatments for cancers, including neuroblastoma, using a combination of the immune system and tiny drug carriers called nanoparticles. In particular, we are interested in creating a therapy using natural killer (NK) cells, which are immune cells that circulate in the body and kill cells that are infected, foreign, or pose a threat to the person’s health. Unlike other types of cancer, neuroblastoma expresses proteins on their cell surface that NK cells recognize as a threat. However, neuroblastoma cells can also secrete molecules, including TGFbeta, to turn off NK cells. The tumor cells also grow so tightly together that NK cells cannot squeeze into the tumor and begin killing. Thus, even though NK cells should be able to kill neuroblastoma cells, these chemical and physical barriers block it.
Rachel Burga, a 2017 ALSF POST award recipient from the Fernandes Lab, focused on developing NK cells to overcome this chemical barrier. She developed TGFbeta-resistant NK cells and showed that they were much more cytotoxic against neuroblastoma cells than regular NK cells. This year, we want to build on Rachel’s work by overcoming the physical barrier: we will use an enzyme called heparanase which can degrade the tumor stroma, in conjunction with the modified NK cells Rachel developed. We think that conjugating heparanase to nanoparticles may increase this degradation by aggregating the heparanase in tumors, orienting the heparanase to maximize its efficacy, and preventing its degradation. These nanoparticles would be administered to the tumor to start its degradation, and shortly therafter, TGFbeta-resistant NK cells would be injected to destroy the tumor. Our goal is to help NK cells overcome the chemical and physical barriers that neuroblastoma poses by using a combination of heparanase and TGFbeta-resistant NK cells.
