On October 24, 2024 Researchers at Children’s Hospital of Philadelphia (CHOP) reported significant findings in the treatment of neuroblastoma, a cancer of the peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen (Press release, CHOP, OCT 24, 2024, View Source [SID1234647385]). The study offers insights that could lead to new, personalized medicine approaches in immunotherapy treatment. The findings were published today in the journal Cancer Cell.

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Neuroblastoma is the most common cancer in infants, accounting for a disproportionate share of pediatric cancer deaths. Currently, monoclonal antibody-based immunotherapy is the only Food and Drug Administration (FDA) approved treatment for neuroblastoma. However, this type of immunotherapy can cause painful side effects, and patients often relapse. All these factors led researchers to seek new and innovative approaches to treating this disease and safely improve cure rates.

In this study, researchers used a multi-omics approach to analyze and identify potential new targets for immunotherapy, integrating proteomic, transcriptomic, and epigenomic data to pinpoint biologically relevant proteins on the surfaces of cancer cells that are visible to the immune system. Reviewing comprehensive data helps scientists understand how cells function and what goes wrong in diseases like cancer.

Based on their findings, the researchers prioritized the protein, Delta-like canonical notch ligand 1 (DLK1). They showed that high expression of DLK1 in cancer cells promotes tumor growth and discovered how neuroblastoma cells increase DLK1 levels. They also found that DLK1 is produced at a higher rate in many childhood and adult cancers.

"Our study demonstrates the power of an integrative multi-omics approach to identify immunotherapeutic targets," said senior author, Sharon J. Diskin, PhD, a member of the Center for Childhood Cancer Research and Department of Biomedical and Health Informatics at CHOP and an Associate Professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

The researchers subsequently studied a novel treatment called ADCT-701, an antibody-drug conjugate (ADC) that delivers a potent therapy targeting DLK1-expressing cancer cells, as part of the National Cancer Institute’s (NCI) Pediatric Preclinical in Vivo Testing (PIVOT) Program. They demonstrated that ADCT-701 was highly effective in eradicating highly resistant patient-derived tumors. The NCI is currently conducting a phase 1 clinical trial for treatment of neuroendocrine neoplasms with ADCT-701 in adults 18 and older.

"Our findings provided important validation and preclinical data to support an ongoing first-in-human DLK1-directed immunotherapy clinical trial for adult patients diagnosed with neuroendocrine neoplasms, including neuroblastoma," said the study’s primary author, Amber Hamilton, PhD, a post-doctoral fellow at CHOP. "This research brings hope to families, offering the potential for more effective treatments."

The research was supported by a grant from the W.W. Smith Charitable Trust, an Innovation Award from Alex’s Lemonade Stand Foundation, and a Stand Up 2 Cancer-St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). This work was also supported by National Institutes of Health (NIH) grants U54-CA232568, R01-CA204974, R01-CA237562, R03-CA230366, U01-CA199287, R35-CA220500, U01-CA263957, U01-CA199222, F31-CA225069 and T32-CA009140. The work was delivered in part by the NexTGen Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100002), the National Cancer Institute (CA278687-01) and The Mark Foundation for Cancer Research.