PA CURE Grant Fuels Childhood Leukemia Research at CHOP

B-cell acute lymphoblastic leukemia (B-ALL) is a type of blood and bone marrow cancer.

Researchers at Children's Hospital of Philadelphia and the University of Pennsylvania are laying the groundwork for next-generation clinical trials of therapies for patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL).

Fueled by a $5 million Pennsylvania Department of Health Commonwealth Universal Research Enhancement program (CURE) grant, they will address critical knowledge gaps in the understanding of the most common pediatric cancer.

"Our multidisciplinary team of scientists and clinicians at CHOP and Penn is excited to pursue this major collaborative investigation using primary leukemia patient samples, next-generation omics technologies, targeted therapies, and cellular immunotherapies," said Sarah K. Tasian, MD a pediatric oncologist and Chief of the Hematologic Malignancies Program at CHOP.

B-ALL is a fast-growing blood cancer that occurs when white blood cells in the bone marrow multiply and mutate. While modern chemotherapy regimens can cure most children with the disease, around 10 to 15% of patients fail to respond to initial treatment or relapse.

Immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy have been lifesaving for some children with relapsed/refractory B-ALL, like Emily Whitehead — the first pediatric patient to receive the revolutionary therapy — in which a patient's own immune cells are genetically altered to find and attack cancer.

However, CAR-T and targeted inhibitor therapies are not successful for all patients, and more work is needed to overcome barriers to the development of effective curative therapies for all children and adolescents with B-ALL.

B-ALL patients' mixed responses to therapies are due, in large part, to the disease's heterogeneity. Tumor cells can differ from one patient to another, and cells within a tumor can change over time.

"Imagine a leukemia as a bowl of different colored candies. The chemotherapy eats up the orange, green, and blue ones, but leaves the few red ones behind," Dr. Tasian said. "What is it about the red candies that keeps them stuck in the bowl?"

In this multi-pronged PA CURE project, the researchers will first use single-cell multi-omics technologies to elucidate the inherent heterogeneity within specific high-risk B-ALL genetic subtypes, as well as identify critical genes and pathways that lead to conventional therapy resistance.

They will then identify new targets potentially amenable to new precision medicine therapies and validate these targets by drug testing sophisticated patient-derived models of high-risk B-ALL subtypes.

In the second part of the project, the team will harness its unique expertise and access to samples from patients treated with CAR T immunotherapy at CHOP to identify biologic factors associated with long-term persistence and cure.

"This project will undoubtedly lead to important new biologic discoveries that will benefit children, adolescents, and young adults with high-risk B-ALL subtypes in the near future," Dr. Tasian said.

The research team includes: Kathrin Bernt, MD; Martin Carroll, MD; Stephan Grupp, MD, PhD; Stephen Hunger, MD; Kai Tan, PhD; David Teachey, MD; and Evan Weber, PhD.

The PA CURE program was established in 2001 by Act 77, and it funds collaborative biomedical research that aims to improve the health of Pennsylvanians.