For families affected by DIPG and DMG, progress in treatment has often felt frustratingly slow. While many experimental therapies have shown early promise, few have been able to overcome the challenges that matter most in real-world care: safety in the brain, durability of response, and the ability to target tumor cells without harming healthy tissue.
One area that continues to evolve is immunotherapy, particularly CAR T-cell therapy. Recent research, funded by The Cure Starts Now and the DIPG/DMG Collaborative and led by Dr. Sujatha Venkataraman at the University of Colorado Denver, focuses on refining this approach to better meet the realities of pediatric brain tumors.
Rather than introducing an entirely new concept, this work builds on lessons learned from earlier CAR T-cell efforts and is designed to directly address why some of those approaches struggled.
Focusing on CAR T-Cells in DIPG and DMG
CAR T-cell therapy uses a patient’s own immune cells, which are engineered to recognize specific features on tumor cells. For DIPG and DMG, this approach remains compelling because immune cells are able to reach the brain when many drugs cannot.
At the same time, applying CAR T-cell therapy to solid brain tumors has proven more complex than in blood cancers. Early studies demonstrated that CAR T-cells could reach tumors and generate responses, but also revealed serious limitations, including toxicity, immune cell exhaustion, and tumor relapse.
Dr. Venkataraman’s research team has focused on redesigning CAR T-cells to address these challenges directly.
Learning From Early Targets
An important early focus of this work was CD99, a marker found at high levels on many DIPG tumor cells. CAR T-cells engineered to recognize CD99 were able to infiltrate tumors and significantly extend survival in preclinical models, confirming that immune-based approaches could impact these tumors.
However, this work also revealed a key limitation. CD99 is not exclusive to tumor cells; it is also present on some normal cells, including immune cells themselves. As a result, CAR T-cells targeting CD99 began attacking one another, limiting how long they could persist and allowing tumors to eventually return.
Rather than abandoning CD99 as a target, Dr. Venkataraman’s research team treated this as a design problem—one that could potentially be solved through greater precision.
Introducing Logic-Gated CAR T-Cells
This led to the development of logic-gated CAR T-cell therapy, a more controlled and selective immune approach.
Unlike traditional CAR T-cells that activate when they recognize a single marker, logic-gated CAR T-cells require two tumor-associated markers to be present at the same time. For DIPG and DMG, these markers are CD99 and B7-H3, which are commonly found together on tumor cells but rarely found together on healthy tissue.
This dual-recognition system functions like a safety lock. Only when both markers are detected does the immune cell fully activate and kill the tumor cell.
This design improves:
- Specificity, reducing off-target effects
- Persistence, preventing immune cells from destroying one another
- Durability, lowering the risk of tumor relapse
What Preclinical Studies Have Shown
In multiple preclinical models of DIPG, logic-gated CAR T-cells demonstrated outcomes that differed meaningfully from earlier approaches.
Researchers observed:
- Complete tumor elimination after a single low dose
- No tumor regrowth during extended observation
- Long-term persistence of CAR T-cells
- Clear discrimination between tumor cells and healthy cells expressing only one marker
These findings suggest that logic-gated CAR T-cells may overcome two of the most significant barriers families have seen with immune therapies: safety concerns and loss of effectiveness over time.
Importantly, the therapy remained effective even in models with high tumor burden, suggesting potential relevance across different stages of disease.
Moving Toward Clinical Testing
With funding from The Cure Starts Now and the DIPG/DMG Collaborative, Dr. Venkataraman’s research team has completed key early development steps, including manufacturing and regulatory preparation.
Plans are underway for a first-in-human clinical trial anticipated to begin in 2026. The treatment will be delivered directly into the brain using an implanted reservoir, allowing for multiple doses over time. This trial design reflects lessons learned from earlier DIPG CAR T-cell studies, where repeated dosing appeared necessary to maintain response.
The initial focus of the trial will be safety and feasibility, while also looking for early biological signals of activity.
Broader Implications
The logic-gated CAR T-cell platform may extend beyond DIPG and DMG. Similar strategies are being explored for other pediatric brain tumors, including aggressive forms of ependymoma.
In related work, researchers are also developing “armored” CAR T-cells, designed to counteract immune suppression created by certain tumors. These approaches aim to strengthen immune responses while maintaining safety.
The long-term goal is not a single universal therapy, but a set of immune strategies tailored to the biology of each tumor type.
Why This Matters to Families
For families, progress is measured not in headlines, but in whether research meaningfully addresses the obstacles that have limited past treatments. This work does not promise a cure — but it does represent a careful, data-driven effort to design something better based on what has been learned.
This research reflects a thoughtful evolution of CAR T-cell therapy, shaped by lessons learned from earlier efforts and made possible through funding from The Cure Starts Now and the DIPG/DMG Collaborative.
For families navigating DIPG and DMG, it represents continued momentum — and a commitment to keep pushing forward.