A Changing Clinical Landscape: Promising Therapeutic Avenues in the Treatment of DIPG and Other Diffuse Midline Gliomas

Mark Souweidane, MD
(Credit: Weill Cornell Medicine)

Diffuse midline gliomas (DMGs) are a heterogeneous group of (mainly) pediatric tumors that affect midline structures (thalami, midbrain, pons, or spinal cord) characterized by glial proliferation and an infiltrative nature that makes them inseparable from nearby brain parenchyma. Patients usually present with a constellation of symptoms owing to tumor location (i.e. contralateral hemiparesis for thalamic lesion or long tract signs and cranial nerve paresis for pontine ones) and obstructive hydrocephalus owing to mass effect on the third or fourth ventricle.

Diagnosis relies on characteristic imaging features observed on contrast-enhanced MRI; in cases of diagnostic uncertainty, biopsy can be performed to guide management. Historically, the treatment of DMGs – of which diffuse intrinsic pontine gliomas (DIPGs) are the most common subtype – has stagnated despite significant improvements in other liquid and solid cancers. Following diagnosis, external beam radiotherapy has remained the mainstay of therapy with significant but short-lived improvements in overall survival.

In the past decade, however, given the increased safety of stereotactic biopsies and the desire for more tissue to be utilized for preclinical studies, a revolution started to take place. Increased tissue availability led to improved understanding of tumor biology and more reliable preclinical models; improved social understanding of the disease and its consequences led to an increase in funding – both at the federal level and through generous private donors – with the ultimate hope to achieve a meaningful clinical improvement.

Numerous landmark studies followed: Mackay and colleagues, for instance, sequenced a thousand DMG samples and identified key mutations pertaining to a worse prognosis. A point mutation on histone H3, for instance, was associated with significantly worse prognosis but, similarly, held therapeutic potential. Subsequent studies assessed the epigenetic vulnerability of DIPG with current clinical trials aiming at normalizing an otherwise aberrant epigenetic landscape.

Umberto Tosi, MD

(Credit: Weill Cornell Medicine)

The explosion in preclinical studies and models led to a parallel increase in clinical trials aimed at improving DMG prognosis. Importantly, these were not focused on a single approach, therapeutic, or drug; rather, multiple studies took place addressing different aspects of DMG’s complex biology. Far from being a comprehensive review of current investigative efforts, current clinical studies can be separated in four broad groups:

• Direct drug delivery: given the inability of most systemic compounds to readily cross the blood-tumor barrier and accumulate at therapeutic levels in the tumor prior to the development of systemic adverse effects, direct drug delivery strategies rely on cannula implantation of tumor parenchyma to achieve high locoregional concentrations with minimal systemic exposure and toxicity. Recent clinical trials have shown the tolerability of this convection-enhanced delivery (CED) approach for both radiolabeled monoclonal antibodies and small molecule histone deacetylase inhibitors, highlighting the importance of infusate monitoring following delivery. Further studies are needed to ascertain whether CED can result in meaningful clinical improvement; however, our group’s early phase clinical trial where a monoclonal antibody was delivered to children with DIPG not only showed the safety of this approach, but also resulted in some promising evidence for long-term survivors. Given this encouraging data, follow-up trials are in development.
• Locoregional blood-tumor barrier opening: the blood-tumor barrier can be opened to maximize therapeutic accumulation within tumor. Early-phase clinical trials are assessing the feasibility of this approach by combining MRI-guided focus ultrasound to open the blood-tumor barrier with intra-arterial drug delivery, which has shown promise in preclinical models.
• Oncolytic virus: given the failure of most systemic chemotherapies, a new oncolytic virus (DNX-2401) has been developed to target DIPG cells and lead to decreased tumor burden via a combination of direct oncolysis, immune activation, and synergy with radiotherapy. A first clinical trial in which this approach was tested in 12 patients showed overall safety and promise for further investigation.
• CAR-T therapy: CAR-T cells, engineered T cells that harbor a chimeric antigen receptor that leads to their activation upon antigen binding, have shown promise in numerous liquid and solid cancers. A subtype of DMG is known to have high levels of expression of disialoganglioside GD2; in a recent clinical trial, 4 patients with DMG underwent intravenous administration of anti-GD2 CAR-T cells, with 3 of them also undergoing intrathecal administration. Overall, with significant intensive care and neurosurgical support (e.g. Ommaya placement for management of hydrocephalus), this study showed the feasibility of this approach.

A success story in DIPG discovery and newfound optimism originates in the alliance between philanthropic dollars and translational investigators. A solid correlation has been witnessed between DIPG-directed philanthropy and scientific discovery. Never before has there been such an abundance of therapeutic trials for pediatric patients with DIPG; renewed hope. A solid example of this partnership is the alliance between Mark Souweidane, MD, of the Children’s Brain Tumor Project and the Cristian Rivera Foundation. This is but one example of how this type of partnership has moved the needle and offered some children additional years beyond expectation. Overall, the last decade has seen a revolutionary change in the understanding of the biology of DMGs and their therapeutic vulnerabilities; hopefully, current studies will be able to improve what remains an otherwise unforgiving prognosis.

REFERENCES
1. Gállego Pérez-Larraya J, Garcia-Moure M, Labiano S, et al. Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma. N Engl J Med. 2022;386(26):2471-2481. doi:10.1056/NEJMoa2202028
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6. Souweidane MM, Bander ED, Zanzonico P, et al. Phase 1 dose-escalation trial using convection-enhanced delivery (CED) of radio-immunotheranostic 124I-Omburtamab for diffuse intrinsic pontine glioma (DIPG). Neuro Oncol. Published online February 19, 2025. doi:10.1093/neuonc/noaf039