Precision Medicine Takes Center Stage

When precision medicine took center stage in 2015, research at The Children’s Hospital of Philadelphia had a starring role. The curtain opened in January with President Obama’s launch of the Precision Medicine Initiative (PMI), which seeks to spur advances in targeted treatments for disease by supporting genomic research, developing a network of patient volunteers, and partnering with academia and industry. The resulting treatments will be considered precise or personalized because they are designed to act on the specific molecular pathway or gene found to underlie the patient’s own disease.

CTL019 Precision Immunotherapy: A Headlining Example

A prime example is an investigational precision immune therapy for cancer developed at the University of Pennsylvania and CHOP, known as CTL019. After attending the PMI launch event, the first pediatric patient to receive this form of chimeric antigen receptor therapy (CART), 10-year-old Emily Whitehead, was highlighted in a White House blog post about Americans whose lives have been changed by precision medicine.

In Emily’s case of acute lymphoblastic leukemia (ALL), her body’s cancerous B-cells were found to have the protein CD19 on their surface. In the investigational CTL019 therapy, she received an infusion of her own T-cells that were extracted and bioengineered in a way intended to attack the CD19 protein and destroy the B-cells.

Over the course of 2015, results from ongoing CHOP investigations added to researchers’ understanding of CTL019. Clinical trial leaders, including Stephan A. Grupp, MD, PhD, a pediatric oncologist at CHOP and professor of Pediatrics at the Perelman School of Medicine at Penn, reported long-term remissions and other outcomes in December at the American Society of Hematology meeting. Another CHOP team revealed one of the cellular tricks B-cells may use to evade this immune therapy. And CHOP researchers continue to develop other CART approaches for other forms of leukemia and for other cancers.

Genomic Discoveries and Tracking Disease Evolution to Find Precision Targets

The larger unfolding story of precision medicine involves many more discoveries from bench to bedside. Ongoing genomic discoveries at CHOP this year, detailed in a separate article in this issue, form the basis for many potential future precision therapies aimed at disease-involved gene variants.

In addition, CHOP researchers made several advances this year in understanding molecular and genomic evolution of relapsed cancers. One CHOP-led team found distinct patterns of cancer-driving mutations in ALL that were generally different at diagnosis than at relapse. This study, published in Nature Communications, was just “the tip of the iceberg” of what is to come from the collaborative childhood-cancer Therapeutically Applicable Research to Generate Effective Therapies (TARGET) study, according to study leader and TARGET-ALL principal investigator Stephen Hunger, MD, chief of the Division of Oncology and director of the Center for Childhood Cancer Research.

Another such study of cancer evolution through relapse, published in Nature Genetics, has direct implications for a potential precision treatment. Researchers from the lab of John M. Maris, MD, demonstrated that relapsed neuroblastoma tumors show frequent mutations in the RAS-MAPK pathway, which existing drugs have already shown promise targeting in cell and animal studies.

From Genomics to Precision Drug Discovery

The fortuitous existence of drugs targeting a disease-associated pathway, as in Dr. Maris’ team’s study, is one of the fastest ways precision medicine can move from genomic discovery to successful treatment. This was the case with a drug targeted to a molecular subgroup of medulloblastoma (brain cancer) that showed preliminary success in a report in the Journal of Clinical Oncology this year, co-authored by CHOP’s Tom Curran, PhD, FRS.

Drugs that target newfound disease biomarkers and mutations are rarely already known, though. In order to keep precision medicine moving forward, drug discovery must keep pace with genomic discovery. Dr. Maris and colleagues called for academic, federal, and industry leaders to develop new models of drug development in an editorial published in JAMA this year. They suggested that the need will grow as “rare diseases become even more rare” once genetically defined subsets are revealed.

Already beginning to fill some of that drug-discovery gap, CHOP and four other high-profile oncology research programs plus a coordinating center joined the new Pediatric Preclinical Testing Consortium (PPTC) launched by the National Cancer Institute (NCI) to help researchers identify drug candidates for pediatric clinical trials. As part of the PPTC, Dr. Maris’ lab uses animal models of neuroblastoma that incorporate genetic material from patient tumor cells, allowing scientists to design drug tests highly tailored to specific, well characterized subtypes of human neuroblastoma tumors.

Taking Treatments Into Trials

Representing the next stage of the process, testing promising precision drugs in clinical trials, this year saw the announcement of Project:EveryChild Pediatric MATCH (Molecular Analysis for Therapy Choice), a trial due to launch in early 2016 and include about 300 children each year with advanced cancers.

“Pediatric MATCH will try to match genomic changes in certain children’s cancers with drugs that are either approved for adult cancers or with drugs that are still under investigation and not yet approved,” said Peter Adamson, MD, a pediatric oncologist at CHOP and chair of the Children’s Oncology Group, the collaboration of more than 220 children’s hospitals that oversees Pediatric MATCH with the NCI and a range of pharmaceutical companies. The trial will also focus on determining the genomic basis for treatment failures.

With new funding from Alex’s Lemonade Stand Foundation, Dr. Maris and Yael Mosse, MD, plan to launch another new trial in 2016 for relapsed neuroblastoma, using an innovative dynamic design to quickly incorporate new treatments matched to the evolving genetic changes in an individual patient’s tumor that they will track through ongoing lab studies of each patient’s cells.

To learn more about the future of precision medicine and how the concept works in practice on diseases other than cancer, look for an article about how precision medicine approaches are being developed in epilepsy research in the January issue of Bench to Bedside.

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