IDO-based Immunotherapy for Pediatric Brain Tumors
This proposal will address a fundamental gap in understanding the specialized immune biology of the brain tumor micro environment through studies of the indoleamine 2,3-dioxygenase (IDO) pathway of immune tolerance. IDO is often co-opted by tumors to escape immune attack. Immunologic therapy of cancer is now a cutting-edge new form of cancer treatment for adults, but has not yet brought benefit to children with cancer. The long-term goal is to establish a pediatric immunotherapy program to translate pediatric-focused laboratory research into Phase I and Phase II immunotherapy trials in children.
The objective of the current proposal is to elucidate the mechanisms by which blocking IDO synergizes with standard chemotherapy and radiation therapy. The proposed research plan builds on preliminary data that intense inflammation plays a key role in tumor destruction when IDO-blockade is combined with chemo-radiation therapy in a mouse brain tumor model.
The central hypothesis is that IDO is a previously unrecognized vascular quiescence factor in tumor biology and that blocking IDO during chemo-radiation therapy leads to rapid immune-mediated vasculitis and tumor destruction; this widespread innate inflammation then serves as a potent stimulant to drive specific and lasting anti-tumor immunity. The rationale for this research is that understanding the mechanisms by which IDO shields tumors from the underlying immune-activating effects of our standard chemo/radiation therapies will allow us to develop new strategies to combine these standard treatments with immunologic therapy.