Multimodal Cell-Free DNA Profiling to Monitor Tumor and Immune Dynamics Across Neuroblastoma Immunotherapy and Targeted Therapy Trials
Cancer therapies such as CAR T cells and targeted ALK drugs can be remarkably effective for some patients, but others do not respond or eventually relapse, and we often do not know why. Our project will develop a next-generation blood test to understand, in detail, how these novel treatments work—or fail to work—by reading signals from tiny fragments of DNA circulating in the bloodstream.
When tumor and immune cells die, they release small pieces of DNA into the blood, called cell-free DNA. By combining information about chemical tags on this DNA (methylation) with patterns in how the DNA is cut and packaged (fragmentomics), we can learn which cells the DNA came from, how much tumor is present, and how the immune system is behaving over time. We will leverage existing stored plasma samples from patients treated with lorlatinib (an ALK-targeted drug) and from patients enrolled on a PHOX2B CAR T-cell trial to develop, optimize, and validate this multimodal assay in real-world clinical settings.
Our long-term goal is to make this assay the key biomarker platform for two upcoming clinical trials testing ALK-directed CAR T cells and new ALK degrader drugs. By tracking cell-free DNA profiles across these studies, we aim to uncover mechanisms of response and resistance and to deeply profile the immune landscape during treatment, ultimately guiding the design and selection of the most effective therapies for patients with neuroblastoma and other childhood cancers.
Project Goals
Neuroblastoma is a childhood cancer that is very hard to cure, and many children either die of the disease or suffer serious long-term side effects. Today, doctors rely on scans and bone marrow tests to see how a child is doing, but these tests can miss tiny amounts of remaining cancer and cannot show early warning signs that treatment is no longer working.
This project will use a blood test to follow both the cancer and the child’s immune system in real time. Tumors and immune cells release small fragments of DNA into the bloodstream, called “cell-free DNA.” By reading not only the mutations in this DNA, but also its chemical marks (methylation) and how it is chopped up (fragmentation), we can build a rich picture of where the DNA comes from, how much tumor is present, how active the immune system is, and whether the cancer is starting to resist treatment.
We will apply this approach to children with neuroblastoma treated on two cutting-edge clinical trials: one using an ALK-targeted pill (lorlatinib) and one using a new PHOX2B-directed CAR T-cell therapy. Our goals are to: 1) develop a blood-based test that can detect minimal residual disease earlier than scans, 2) understand which immune responses are linked to strong, lasting remissions, and 3) find DNA “signatures” that signal resistance before the cancer visibly returns. In the future, these tests could help doctors adjust treatment sooner, spare children from unnecessary toxicity and improve chances of cure.
