Collaborative team receives NCI grant to study how to improve immunotherapy for diffuse midline gliomas

Each year, approximately 200 to 300 children in the United States are diagnosed with diffuse midline gliomas (DMG), a tumor that begins in the brain or spinal cord.

The tumors cannot be removed through surgery due to their location in the brain, and current treatments are not effective and lead to a nearly zero percent survival rate.

The University of Cincinnati's Timothy Phoenix is part of a multi-investigator collaborative team with St. Jude Children's Research Hospital's Stephen Mack, PhD, and Giedre Krenciute, PhD, that received a nearly $4 million National Cancer Institute (NCI) grant to study how to improve immunotherapy treatments for DMGs. The trio will test if using a single target can both weaken tumors and strengthen immune cells fighting the cancer, leading to more effective treatment.

CAR-T basics

Immunotherapy treatments train the body's own immune cells to fight cancer, and Phoenix and his colleagues are studying a particular type of immunotherapy called CAR-T therapy. Immune cells called T-cells are harvested from a patient and then genetically modified to target cancer cells.

When you put them back into the patient, those cells will go and try to find that target and then engage with them and try to kill the cancer cells. In DMG patients, CAR-T-cell clinical trials have shown some promise in terms of there being some response from patients initially, but it has been variable and is usually not durable or a curative therapy."

Timothy Phoenix, PhD, a University of Cincinnati Cancer Center researcher and associate professor in UC's James L. Winkle College of Pharmacy

Research plan

When giving immunotherapy treatments, different tumors are referred to as being "hot," meaning immune cells are present in the tumors, or "cold," meaning immune cells are excluded from the tumor.

Phoenix said DMGs are thought to be cold, so one potential way to make CAR-T more effective is to "heat up" the tumor and make them more likely to attract immune cells. Prior work by St. Jude's Mack found that inhibiting a process called DNA methylation in DMG cells could potentially make these tumor cells attract more immune cells, so the team is testing if this happens with different DMG models.

"There is very little known about how immune cells interact with brain tumors, and even less known about how changes in these interactions impact immunotherapies like CAR-T cells," Phoenix said. "Would CAR-T cells be more attracted to the tumor, and would it improve their ability to kill tumor cells?"

Another issue with CAR-T therapy is that the immune cells quickly become exhausted and no longer work. St. Jude's Krenciute has found blocking DNA methylation in the T-cells gives them more endurance and makes them more effective for longer, meaning inhibiting DNA methylation may not only be beneficial in tumor cells but also in CAR-T cells.

UC's Phoenix has developed unique DMG animal models the team will use to test how targeting DNA methylation affects DMG and CAR-T cells.

"If you put it all together, now you have a single target (DNA methylation) in two different populations of cells," Phoenix said. "Targeting it in tumor cells could change the microenvironment and make it more attractive to immune cells coming in, and targeting it in the CAR-T-cells themselves could make them work better. Combining both together has the potential to supercharge things, we hope."

According to Phoenix, it is not common for a single target to both weaken a tumor and improve the treatment.

"This is something that is relevant for a lot of drug targets but people only tend to look at one cell of interest," he said. "This is why a larger collaborative team is really necessary. Having multiple groups with unique expertise working together gives us the ability to view these topics with different perspectives and strengthens the overall science."

Pediatric Immunotherapy Network

This research project is one of six that make up a new NCI Pediatric Immunotherapy Network, an initiative that aims to address current challenges in pediatric immuno-oncology and accelerate the development of effective immunotherapies for pediatric solid tumors.

The network is an expansion of a previous pediatric immunotherapy research collaboration funded by the U.S. National Cancer Institute's Cancer Moonshot, a program that marshals resources across the federal government to speed progress in cancer research and lead to improved cancer prevention.

All of the researchers that make up the network recently met at NCI headquarters for a kickoff meeting and will continue to meet to share scientific data, ideas and resources to promote collaboration and maximize the impact of each project.

"It'll be great to interact with these other world-class research teams in the [network] and receive feedback as we continue with this project," Phoenix said. "In the first meeting we were already discussing ways to interact and collaborate between groups. I'm excited our team is part of [this] and has this opportunity to contribute towards improving outcomes for patients."