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