ALK as an Immunotherapeutic Target in Neuroblastoma
Background
Despite progress, many children currently diagnosed with cancer have less than a 50% chance of survival and these rates have plateaued over the last decade. In addition, current standard therapies are exceedingly toxic, leaving childhood cancer survivors with life threatening morbidities. Although our understanding of the biology of childhood cancer has advanced substantially over the last two decades, new precision therapies have not yet significantly improved childhood cancer outcomes. Neuroblastoma (NB), an embryonal malignancy of the developing sympathetic nervous system, remains a devastating clinical problem as it continues to be a leading cause of childhood cancer morbidity and mortality despite dramatic increases in chemoradiotherapy intensity. Proof-of-concept that immunotherapy can be effective in this disease was fairly recently demonstrated in a phase 3 trial using a chimeric monoclonal antibody that targets the disialoganglioside GD2 typically present on the surface of NB cells. However, this is a very toxic therapy with dose limiting pain and anaphylaxis common and relapse still occurs commonly during or after immunotherapy, such that overall survival is not impacted in at least half of patients. We discovered heritable activating mutations in the anaplastic lymphoma kinase (ALK) oncogene in NB pedigrees and we and others have shown that oncogenic ALK mutations are the most common somatically acquired single nucleotide variants at diagnosis and relapse. These mutations activate kinase activity, but several de novo resistance mutations inhibit the ability of available tyrosine kinase inhibitors to abrogate ALK signaling, potentially limiting their utility in this disease. Importantly, our studies have shown that native ALK protein is expressed on the surface of the majority of NB cells with or without ALK mutations, but not on normal tissues, providing an opportunity for development of immunotherapeutic strategies. Clinically relevant antibodies for this target, as opposed to other kinases such as EGFR and HER2/ERBB2, have not yet been developed. Furthermore, we have unpublished preliminary data presented herein that ALK is expressed in a subset of several high-risk pediatric solid tumors, suggesting a broader role for ALK-directed immunotherapies.
Project Goal
We plan to generate immunotherapeutic strategies that exploit tumor-specific ALK expression and expect to show potent efficacy in relevant cellular and murine models of high-risk ALK-expressing pediatric cancers. In addition, we will define a responder hypothesis for stratification of patients to an anti-ALK immunotherapeutic approach.
Mentored by Dr. Yael Mossé
Children’s Hospital of Philadelphia, Philadelphia, PA
