Immunotherapy for the treatment of diffuse intrinsic pontine glioma: a paradigm-shift in opportunity

Brainstem glioma is a heterogeneous group of tumors that comprise diffuse intrinsic pontine glioma (DIPG), glioblastoma, diffuse astrocytoma, oligodendroglioma, and pilocytic astrocytoma, that occur in the midbrain, pons, and medulla. DIPG is a type of tumor that initiates in the pons and is distinguished by diffuse infiltration, poor demarcation from normal tissues, and frequent invasion of distant brain regions. Significant excision is impossible due to its fragile anatomical location. DIPG is thought to account for approximately 75% of pediatric brainstem tumors [1,2].

Present scenario

DIPG is diagnosed based on clinical signs such as ataxia, pyramidal tract dysfunction, and palsy of the abducens nerve (cranial nerve VI). At present, the most powerful tool for the clinical diagnosis of DIPG is magnetic resonance imaging (MRI). DIPG patients are typically treated with focal radiation therapy, mainly because surgery and current chemotherapeutic treatments failed to add any clinical value. Chemotherapy is typically utilized as adjuvant therapy. Radiation therapy provides symptomatic relief in 70-80% of patients and is thus primarily regarded as a palliative measure [3].

In DIPG patients, however, survival rates remain depressing. Adult studies on infiltrating brainstem gliomas show an average survival of 30-40 months, while the average survival in pediatric DIPG is 10–12 months. Treatment becomes much more difficult in the case of an inoperable tumor with high-grade pathology. Even so, despite recent advances in anti-glioma therapies, the prognosis of patients remains dismal [1].

DIPGs frequently cause rapid local infiltration, and about 20% of DIPG patients develop neuraxis metastases. Decades of research have failed to produce a treatment outcome with any apparent survival gain since various hurdles impede the effectiveness of DIPG research and therapy. Along with the aggressive nature of the disease, its fragile anatomical location in the brainstem and immunological senescence further limits therapeutic perspectives [2,3].

Will immunotherapy help DIPG patients?

The immune system implements a cascade of complex mechanisms for the recognition and elimination of cancer cells. These pathways could theoretically impede the progression of malignant tumors. However, cancer cells that survive immune screening accelerate the disease process by escaping the host's anti-tumor immunological response. Cancer immunotherapy is based on reactivating anti-tumor immune responses and bypassing immunological escape pathways [2,3].

Immunotherapy has evolved as a novel therapeutic approach for both solid and hematological tumors, and it has become the standard of care for many adult and pediatric cancers. The relevance and efficacy of immunomodulatory treatment techniques for DIPG patients, however, are yet to be proved. At present the most often used immunotherapies for DIPG are [2,3]:

• Checkpoint inhibitors

• Chimeric antigen receptor (CAR-T) cells

• Vaccine therapy

• Oncolytic viruses

Checkpoint inhibitors

Immune checkpoint inhibitors are one of the earliest types of cancer immunotherapy that can improve anti-tumoral adaptive immunity by restoring cytotoxic T-cell function. At present, the most common immune checkpoint inhibitors in clinical practice utilize antibodies against:

• Programmed cell death protein-1 (PD-1)

• Programmed cell death ligand protein-1 (PD-L1)

• Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4).

These and other proteins are involved in the primary decline of T-cell activity, which is critical in tumor-mediated immunosuppression. The efficacy of checkpoint inhibitors in other solid tumors, most notably metastatic melanoma, has sparked considerable interest in their use in pediatric brain tumors like DIPGs. Regrettably, patients with DIPG did not benefit much from the checkpoint inhibitor treatment in terms of survival [2,3].

CAR-T cells

CARs have the potential to redirect T-cells to specific antigens. The activated T-cells that are infused into patients kill cells that display certain antigens. Given the ineffectiveness of immune checkpoint inhibitors in DIPG, CAR-T-cell therapy can be a better treatment option. Nowadays, several DIPG antigens, including IL13Rα2, GD2, EGFRvIII, and B7-H3 have been developed as CAR-T-specific recognition antigens. The most representative and effective intervention is GD2 (disialoganglioside) CAR-T-cell therapy [2,3].

Vaccine therapy

Cancer vaccines, as a new immunotherapy approach, have increasingly drawn the attention of researchers in recent years. Cancer vaccine therapy is based on countering immunological tolerance by stimulating the immune system with foreign antigens (cancer-specific DNA, mRNA, or polypeptide chains) to reactivate the immune system and trigger an immune response against the tumor. Peptide cancer vaccines elicited a distinct immune response and improved clinical outcomes in children with malignant brainstem and non-brainstem gliomas.

Furthermore, peptide vaccines that specifically target H3K27M-specific proteins have been shown to be effective in clinical trials and successful in preclinical studies of DIPG. Furthermore, autologous dendritic cell vaccines showed negligible toxicity in normal cells while improving clinical response [2,3]. A clinical trial (Identifier: NCT03396575) is currently underway to assess the feasibility and safety of autologous dendritic cell vaccines [4].

Oncolytic viruses

Oncolytic viruses are intended to target and destroy cancer cells with minimal harm to healthy cells. Infection with the oncolytic virus and the subsequent destruction of cancer cells results in the release of enormous amounts of antigens that evoke anti-tumor immunity. Two oncolytic viruses are currently being developed for the treatment of pediatric gliomas (containing DIPG). The first is adenovirus DNX-2401 (delta-24-RGD), which was initially shown to be safe and effective in an immunocompetent DIPG mice model by targeting and destroying DIPG cells while also triggering an immune response [2,3]. A succeeding clinical trial (Identifier: NCT03178032) confirmed its therapeutic efficacy [5]. Another oncolytic virus, herpes simplex virus 1716 (HSV1716), has been demonstrated to have anti-DIPG potential with a favorable non-tumor tissue safety profile [2,3].

Immunotherapy for DIPG: where are we headed?

Inadequate study of the DIPG immune milieu is now a barrier to the deployment of immunotherapeutic approaches. More research on immunotherapies for DIPG is needed to optimize the strength of innate and adaptive anti-tumor immune responses while limiting their potential damage in this anatomically fragile location.

References

1. Morimoto, T. et al. 'Combined Treatment With Radiotherapy and Immunotherapy for Isocitrate Dehydrogenase Mutant Brainstem Glioma in Adult: A Case Report'. Brain Tumor Res Treat. (2022) 10(2), 129–133. DOI: 10.14791/btrt.2022.0009.

2. Bernstock, J.D. et al. 'Immunotherapy approaches for the treatment of diffuse midline gliomas'. Oncoimmunology. (2022) 11(1), 2124058. DOI: 10.1080/2162402X.2022.2124058.

3. Liu, G. et al. 'Immunogenic Cell Death Enhances Immunotherapy of Diffuse Intrinsic Pontine Glioma: From Preclinical to Clinical Studies'. Pharmaceutics. (2022) 14(9), 1762. DOI: 10.3390/pharmaceutics14091762.

4. University of Florida. 'BRAVO: Newly-Diagnosed Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Recovery From Focal Radiotherapy Alone or Focal Radiotherapy and Dose-intensified Temozolomide (Phase I)' [https://clinicaltrials.gov/ct2/show/NCT03396575]. clinicaltrials.gov.

5. Clinica Universidad de Navarra, Universidad de Navarra. 'Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma Newly Diagnosed in Pediatric Patients.' [https://clinicaltrials.gov/ct2/show/NCT03178032]. clinicaltrials.gov.