DIPG / DMG Collaborative

Research Update: The intrinsic and microenvironmental features of diffuse midline glioma: Implications for the development of effective immunotherapeutic treatment strategies

Matthew Dun.jpg
Dr. Matt Dun, Associate Professor, Newcastle

The following study was funded in part by the DIPG/DMG Collaborative:


Diffuse midline glioma (DMG), including those of the brainstem (diffuse intrinsic pontine glioma), are pediatric tumors of the central nervous system (CNS). Recognized as the most lethal of all childhood cancers, palliative radiotherapy remains the only proven treatment option, however, even for those that respond, survival is only temporarily extended. DMG harbor an immunologically “cold” tumor microenvironment (TME) with few infiltrating immune cells. The mechanisms underpinning the cold TME are not well understood. Low expression levels of immune checkpoint proteins, including PD-1, PD-L1, and CTLA-4, are recurring features of DMG and likely contribute to the lack of response to immune checkpoint inhibitors (ICIs). The unique epigenetic signatures (including stem cell-like methylation patterns), a low tumor mutational burden, and recurring somatic mutations (H3K27M, TP53ACVR1MYC, and PIK3CA), possibly play a role in the reduced efficacy of traditional immunotherapies. Therefore, to circumvent the lack of efficacy thus far seen for the use of ICIs, adoptive cell transfer (including chimeric antigen receptor T cells) and the use of oncolytic viruses, are currently being evaluated for the treatment of DMG. It remains an absolute imperative that we improve our understanding of DMG’s intrinsic and TME features if patients are to realize the potential benefits offered by these sophisticated treatments. Herein, we summarize the limitations of immunotherapeutic approaches, highlight the emerging safety and clinical efficacy shown for sophisticated cell-based therapies, as well as the evolving knowledge underpinning the DMG-immune axis, to guide the development of immunotherapies that we hope will improve outcomes.


Despite 50 years of research, survival for patients diagnosed with DIPG remains just 9-11 months. Patients diagnosed with all forms of DMG are told “there are no treatments.” IO strategies have shown great promise in extending survival for cancers of other origins, but similar benefit is yet to be realized in the DMG setting. The unique epigenetic landscape, inter- and intra-somatic heterogeneity, and immunologically cold TME of DMG, highlight areas of research that require focused attention if we are to exploit the potential of immunotherapeutic approaches for patients with DMG. We believe that although limited response to ICI has been seen thus far, combinations with precision therapies may prove to increase response rates. Furthermore, introducing active immune cells with a specific target to the vicinity of the tumor using ACT is proving to be more beneficial at the current time. Accordingly, CAR T cells, as well as vaccines and oncolytic viruses show promising early-stage results. However, there remains a considerable knowledge gap regarding the immune microenvironment of DMG, hampering the development of successful strategies for patients presently fighting DMG. Future work focused on elucidating the underpinnings of the cold immunological response in DMG is desperately necessary, as well as investigations to reveal the potential expression of other (targetable) immune checkpoints. The role H3K27M plays in immunosuppression, and the potential for immunopeptidomics studies using biopsy samples may arm us with novel CAR T-cell therapies that show greater efficacy and specificity. Finally, assessing what roles the various combinations of driver and passenger mutations (including germline) play in the DMG-immune axis is critical. These data will provide us with the potential to co-target these mutations in combination with immunotherapies, to improve response rates, and to better inform which patients will benefit from these sophisticated regimens. Harnessing this information in the development of combination treatment modalities is necessary if we are to improve the likelihood of achieving long-term patient survival for children and young adults diagnosed with DMG.

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