Immunotherapy approaches for the treatment of diffuse midline gliomas

Abstract

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.

Modeling of intracranial tumor treating fields for the treatment of complex high-grade gliomas

“…Certain challenging cases, such as thalamic or brainstem GBMs, are often unresectable due to the involvement of eloquent and/or critical brain structures. In such cases, prognosis is even worse, with median survivals of only 12.2 months having been documented in patients with thalamic GBM 28 , 6 months for brainstem GBM 29 , and approximately 12 months for pediatric diffuse intrinsic pontine glioma (DIPG) 30 . As we have demonstrated despite attempts at optimization of electrode placement and skull reduction surgery, tumors located deep within the brain remain elusive targets for transcranial TTFs.…”

Positioning Transclival Tumor-Treating Fields for the Treatment of Diffuse Intrinsic Pontine Gliomas

“…In addition to the additive effects of TTF noted in combination with chemotherapy and radiation, TTF may also play an important role as an adjuvant treatment in immunotherapy trials by stabilizing tumor progression, thereby allowing patients to mount an immune response [ 6 , 14 ]. This is particularly relevant given the recent flurry of exciting results in the immunotherapy sphere for DIPG [ 6 , 7 , 8 , 25 ]. TTF are capable of stimulating antitumor immunity properties, which may further produce a synergistic effect in combination with immunotherapies [ 25 ].…”

“…As such, the prognosis remains dismal, with a 2-year survival rate of <10% despite maximal radiotherapy [ 1 , 3 ]. A litany of experimental therapeutics is being trialed for DIPG, with some encouraging early results having recently emerged from clinical trials utilizing adoptive cell transfer and immunovirotherapy [ 4 , 5 , 6 , 7 , 8 ].…”

Clinical experience with immunotherapy in patients with diffuse intrinsic pontine glioma

“…For this type of tumour, it appears that combined therapy16 17 with other conventional treatments (chemotherapy and radiotherapy) is needed for best results. ICI cannot be administered first-line when there is a low presence of T-cells in the tumour microenvironment.…”