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.

Keywords: Virotherapy; cell-based therapy; diffuse intrinsic pontine glioma (DIPG); diffuse midline gliomas (DMG); glioma; immune checkpoint inhibition (ICI); immunotherapy; pediatric neuro-oncology; pediatric neurosurgery; vaccination.

Figure 1.

Immunotherapeutic and combination therapy modalities in DMG. DMGs are highly aggressive and often fatal tumors of the pediatric central nervous system. As the anatomical location of these tumors precludes total surgical resection, chemo- and radiotherapies comprise the current mainstays of treatment. Unfortunately, these treatment modalities have not significantly improved the dismal prognoses of DMGs, underscoring the urgency of identifying efficacious alternatives. Obstacles to therapeutic development include addressing intra- and intertumoral heterogeneity, overcoming blood-brain barrier penetrance, and modulating the relatively “cold” immune environment of DMGs. Despite these obstacles, emerging evidence demonstrates strong potential for immune checkpoint blockade, adoptive cell transfer, oncolytic viral therapies, and tumor vaccines as novel therapies for DMG. Pre-clinical studies and clinical trials are also interrogating the synergistic effects of these immunotherapies with chemotherapy and radiotherapy.

Figure 2.

Generation of CAR-T cells for anti-DMG therapy. CAR-T cells present a powerful new approach to precision immunotherapy in DMG. CAR-T cells are generated from a DMG patient’s own T cells (a) and directed against tumor-specific antigens/neoantigens by genetic introduction of a chimeric antigen receptor (CAR) gene (b). Clonally expanded CAR T cells (c) are then reinfused into the originating patient and are activated to promote enhanced tumor cell-specific destruction (d). Treatment of 4 DMG patients with GD2-directed CAR-T cells recently demonstrated both radiologic and clinical benefit, evidencing the transformative potential of this novel therapy.

Figure 3.

Mechanisms of DMG targeting by immunovirotherapy. Oncolytic viruses (OV) are promising novel therapies for DMG as they can be delivered directly via intratumoral injection (a), bypassing the BBB. OV entry (b) and replication (c) within DMG cells induces direct oncolysis and release of new viral particles into the tumor bed, facilitating further inoculation and lysis of surrounding tumor cells (d). Tumor cell debris increases the exposure of the patient’s immune system to both existing and novel tumor antigens, bolstering immune-mediated anti-tumoral effects.

Figure 4.

Combination vaccination therapy and/or immune checkpoint blockade in DMG. a) Cancer vaccination exposes dendritic cells to tumor-specific antigens which are ultimately presented to T cells in secondary lymphoid organs, activating cytotoxic CD8⁺ T cells and thereby promoting their migration into the tumor microenvironment. b) Immune checkpoint proteins (e.g., those expressed on DMG cells) bind to receptors on infiltrating lymphocytes, promoting T cell anergy and resistance to immunotherapy. Combining cancer vaccination with immune checkpoint blockade (ICB) inhibits such immunosuppressive interactions, facilitating anti-tumoral inflammation and therefore cancer cell destruction. Current ICB targets in DMG include the PD-1/PD-L1, CD47/SIRPa, and IDO axes.