CHOP Researchers Identify New Immunotherapy Target in Neuroblastoma and Other Cancers

Researchers at Children's Hospital of Philadelphia (CHOP) have made substantial progress in the fight against neuroblastoma, a type of cancer that affects the peripheral nervous system and is predominantly found as a solid tumor in children's chest or abdomen. These findings, which were published in the journal Cancer Cell, pave the way for new, personalized immunotherapy treatments.

Neuroblastoma is the most frequent cancer in infants and is responsible for a significant number of pediatric cancer deaths. At present, the only Food and Drug Administration (FDA) approved treatment for neuroblastoma is monoclonal antibody-based immunotherapy. This treatment, however, can lead to severe side effects and frequent relapse, prompting researchers to explore more effective and safer treatment options.

In their study, the researchers adopted an advanced multi-omics approach to identify new immunotherapy targets. They examined proteomic, transcriptomic, and epigenomic data to detect relevant proteins on cancer cell surfaces that the immune system can recognize. This comprehensive analysis allows scientists to gain a deeper understanding of cellular functions and the malfunctions that occur in diseases like cancer.

The study highlighted Delta-like canonical notch ligand 1 (DLK1) as a crucial protein. Researchers discovered that increased DLK1 expression in cancer cells aids tumor growth and identified the mechanisms by which neuroblastoma cells elevate DLK1 levels. They also observed that DLK1 production is higher in many childhood and adult cancers.

Dr. Sharon J. Diskin, a senior author of the study and a member of the Center for Childhood Cancer Research at CHOP, emphasized the significance of their integrative multi-omics approach in identifying targets for immunotherapy. Dr. Diskin also serves as an Associate Professor of Pediatrics at the University of Pennsylvania's Perelman School of Medicine.

The research team evaluated a new treatment known as ADCT-701, an antibody-drug conjugate (ADC), as part of the National Cancer Institute's (NCI) Pediatric Preclinical in Vivo Testing (PIVOT) Program. This ADC targets DLK1-expressing cancer cells and delivers potent therapy directly to them. The results showed that ADCT-701 was highly effective in eradicating resistant patient-derived tumors. The NCI is currently conducting a phase 1 clinical trial of ADCT-701 for treating neuroendocrine neoplasms in adults.

Primary author Amber Hamilton, PhD, a post-doctoral fellow at CHOP, stated that their findings provide critical preclinical data supporting the ongoing clinical trial for DLK1-directed immunotherapy in adults with neuroendocrine neoplasms, including neuroblastoma. This research offers hope for more effective treatments for affected families.

The study received support from several grants, including those from the W.W. Smith Charitable Trust, Alex's Lemonade Stand Foundation, and Stand Up 2 Cancer-St. Baldrick's Pediatric Dream Team Translational Research Grant. Additionally, it was supported by National Institutes of Health (NIH) grants and the NexTGen Cancer Grand Challenges partnership, funded by Cancer Research UK, the National Cancer Institute, and The Mark Foundation for Cancer Research.

This research underscores the potential of innovative treatments in combating neuroblastoma and emphasizes the importance of ongoing scientific endeavors to improve pediatric cancer care.