Overcoming Immune Escape Mechanisms in Immunotherapy of Neuroblastoma
Abstract
Scientific Objective and Rationale: Cancer is the number one cause of non-accidental death in children. Neuroblastoma is the most common solid tumor of the body in children, with about 800 new cases diagnosed in the United States in 2015, including children of active duty military personnel. Almost half of these children will be diagnosed with high-risk disease. Despite receiving aggressive combinations of chemotherapy, radiation, bone marrow transplantation, and immunotherapy, these children have less than a 50% chance of surviving. The past 30 years of maximizing the intensity of chemotherapy and radiation has led only to marginal increases in survival. We believe that the answer to improving the survival of these children is in optimizing immune responses against neuroblastoma and overcoming ways that neuroblastoma escapes the immune system. We propose that treatment of neuroblastoma will be more effective if highly functional activated NK cells are present in large numbers, if the NK cells are able to engage neuroblastoma through specific targets, and if NK cells are not suppressed by the tumor or the tissue around the tumor. To accomplish this, we have developed a system of removing, growing, and returning NK cells to neuroblastoma patients. We have initiated a clinical trial that is testing these NK cells combined with one drug that directs them to a target called GD2, and another drug that helps overcome some of the suppressive factors the tumor makes against NK cells. This grant will look closely at samples from this trial to determine how well it is working and identify areas that still need improvement. At the same time, we will be developing several improvements in the laboratory. In case the NK cells that we are delivering do not last very long in patients, we are testing whether a new protein, ALT-803, can be delivered to push the NK cells to survive, grow, and function better. In case the GD2 does not work as a target for all patients, or leaves residual tumor that has escaped without GD2, we will be testing another target called ROR1. In case we find that the NK cells are suppressed by the tumor, we are testing several ways to overcome that suppression. Applicability: The results of the laboratory work performed by the team in this grant proposal can quickly be applied to new clinical trials for children through their involvement in the New Advances for Neuroblastoma Consortium (NANT). The investigators in this Translational Team have decades of experience in developing such clinical trials for children. Military Benefit: This proposal addresses childhood neuroblastoma, the most common solid tumor of the body in children and has poor survival rates. In addition to the direct impact of illness and death, the high side effects and long course of treatment have a severe effect on the parents and family in financial resources, time, and emotional energy, which impact the integrity of the family itself. Such strain on the family may be even more acutely experienced by those in the military when considering the additional stressors already present therein. The findings of our research may also apply to other cancers that are sensitive to NK cells or have similar tumor targets or similar ways of escaping the immune system. This includes other cancers that are important to the military such as skin cancers, colon cancer, and pancreatic cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710420
Entities
People
- Dean Lee
Organizations
- United States Army