Im-07 * Nk Cell Immunotherapy for Pediatric Brain Tumors: Overcoming Resistance to Expand Therapeutic Success

Abstract

Pediatric brain tumors including medulloblastomas and ATRTs are associated with significant mortality and morbidity. Much of this morbidity is due to conventional treatments: radiation and chemotherapy. Therefore, there is an urgent need to develop new therapeutic options to combat these devastating diseases. Immunotherapy has gained traction as a potential alternative to current treatments. Because many immunotherapies rely on the presence of tumor-associated antigens (TAAs) and pediatric brain tumors have poorly defined antigen profiles, we pursued the development of natural killer (NK) cells, which don't require TAAs for their activity, to treat these malignancies. Our work shows that most medulloblastoma and ATRT cell lines are sensitive to NK cell lysis in vitro. Furthermore, both intratumoral NK cell injections as well as infusion at a distant site limit the medulloblastoma growth in mouse orthotopic xenograft models, indicating NK cell trafficking through the brain. These results have provided the foundation for a FDA-approved Phase I clinical trial to infuse NK cells directly into the fourth ventricle of patients who have undergone re-resection of infratentorial tumors. The trial is scheduled to enroll patients in February 2015. Interestingly, our pre-clinical data has also identified overexpression of a novel tumor-secreted immunosuppressive molecule, which was originally shown to confer cardio-protection following myocardial ischemia, in human ATRT samples, and its involvement in promoting resistance to NK cell-mediated lysis. In conclusion, our findings have paved the way for a first in pediatrics brain tumor immunotherapy trial that merges two cutting edge technologies: immunotherapy and loco-regional therapeutics delivery. Our study also offers a novel biomarker for predicting patient response to NK therapy.