Bridging Community and Academic Practice: Multidisciplinary Approaches to Diffuse Midline Gliomas - Episode 11
Emerging Therapies in H3K27M-Mutant DMG
Experts discuss the potential and challenges of CAR-T therapy targeting GD2 for diffuse midline gliomas with H3K27M mutations, highlighting promising but often short-lived responses, significant safety concerns—especially in critical brain regions—and the need for biomarker-driven patient selection to optimize benefits and minimize risks.
Funding support provided by Chimerix/Jazz Pharmaceuticals. Content independently developed and published by OncLive.
Chimeric antigen receptor-modified T cell (CAR-T) therapy targeting GD2 is being explored as a potential treatment for diffuse midline gliomas with H3K27M mutations. Early-phase trials have shown that directing engineered T cells toward tumor-specific markers can produce striking radiographic responses. However, major challenges remain, particularly in determining how best to deliver these cells—whether systemically, directly into the tumor cavity, or into cerebrospinal fluid. While some initial studies reported rapid responses, these effects were often short-lived, and the regimens were associated with significant toxicities, including severe inflammation requiring intensive care and CSF diversion procedures.
Safety remains a central concern in applying CAR-T to diffuse midline gliomas, especially in pediatric brainstem tumors such as DIPG. In these cases, even minor inflammation or edema from treatment can be life-threatening due to the critical location. This has led to the development of a specialized toxicity grading system, tumor inflammation-associated neurotoxicity, to better characterize and manage risks. In adult glioblastoma, where tumors are hemispheric and located in less constrained regions, toxicity profiles differ, though they remain a concern. The balance between potential therapeutic benefit and risk of life-threatening complications underscores the complexity of using CAR-T in these patients.
Despite limitations, CAR-T trials have documented not only short-lived but also occasional durable partial and complete responses, highlighting its promise. Because treatment is highly complex, expensive, and often risky, future efforts must focus on identifying biomarkers to predict which patients are most likely to benefit. This ability to determine responders in advance could shift CAR-T therapy from an experimental intervention into a more targeted and rational component of diffuse midline glioma treatment.
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