This proposal is designed to catalyze the translation of novel immunotherapies for children with cancers of the nervous system. While the Mossé and Maris research programs have traditionally focused on neuroblastoma, a cancer of nerves outside of the brain, both labs have recently extended their research to pediatric brain tumors. This was a natural next step as these cancers share several mechanisms for arising in the first place and also being so aggressive. We have shown that childhood nervous system cancers at their core arise due to defects in normal nervous system development and understanding how these process that are only supposed to be “on” during fetal development and “off” after birth become locked in as part of these malignancies. Most importantly, we have learned how to leverage these “oncofetal” abnormalities that may be the Achilles heel of cancer into new therapies. Here we propose two parallel, but integrated and complimentary Projects designed to create new immunotherapies for children with high-risk nervous system cancers.

Project 1 will develop chimeric antigen receptor (CAR) T cell therapies direct to the anaplastic lymphoma kinase (ALK) protein. The Mossé lab has focused on this protein for almost two decades since discovering ALK mutations both cause neuroblastoma in rare hereditary cases and also the most commonly mutated gene in the most aggressive neuroblastomas. Importantly, the lab has shown that essentially all neuroblastomas express the protein on the tumor cell surface, as do many pediatric brain cancers. ALK is a true “oncofetal” protein and since it is not expressed on normal cells after birth, it thus is an ideal immunotherapy target. Here, we show extensive unpublished preliminary data on the early development of candidate ALK-directed CAR T cells and now will perform the required Food and Drug Administration (FDA) laboratory studies required to deliver a clinical trial within the time-frame of this three year grant.

Project 2 will focus on discovering and developing immunotherapies for a different type of CAR T target. The Maris lab has shown that pieces of the most fundamental proteins that cause childhood cancers can be presented to the immune system through the natural “human leukocyte antigen” system. We have already translated the first such so called “peptide-centric” CAR T cell therapeutic to a clinical trial for neuroblastoma. Here we will leverage extensive unpublished preliminary data to develop 2-3 additional PC-CARs applicable to pediatric peripheral and central nervous systems cancers. We anticipate performing the critical FDA studies necessary for clinical trials in years 2-3 of this grant.

Importantly, both Projects will deliver therapeutics with several adult cancer indications, enhancing our ability to commercialize our therapeutics and thus making them broadly available to children. This project will advance the development of a new class of immunotherapies and accelerate our timelines to new clinical trials that will be in children without first being tested in adults. We think that these new therapies have curative potential.