H3K27M-specific Immune Effector Cells Targeting DMG/DIPG

Diffuse midline glioma or Diffuse Intrinsic Pontine Glioma (DIPG) represent one of the most devastating pediatric central nervous system malignancies. Despite decades of clinical investigation, the standard of care remains focal radiotherapy, which offers only transient symptomatic improvement without altering the uniformly fatal disease trajectory. The median overall survival remains approximately 11 months from diagnosis, with five-year overall survival below 1%. No effective salvage therapies exist following disease progression, and conventional cytotoxic chemotherapy has failed to improve outcomes. The identification of the clonal H3K27M mutation in histone H3 as a driver of tumorigenesis has provided a unique tumor-specific antigenic target, distinguishing this entity from adult high-grade gliomas and opening avenues for innovative precision immunotherapy.

The H3K27M mutation serves as an ideal immunotherapeutic target due to its uniform expression across tumor cells, its absence in normal healthy tissues, and its critical role in oncogenesis. This study incorporates the production and adoptive transfer of autologous H3K27M-specific EIEs. Peripheral blood mononuclear cells (PBMCs) are collected via leukapheresis and stimulated with H3K27M antigen primed autologous dendritic cells. The resultant EIEs phenotypically characterized for CD8+, CD4+ and CD56+ predominance with antigen specificity. Here, the study aims to evaluate the safety and efficacy of the H3K27M-specific EIEs in DMG/DIPG patients.

Inclusion criteria

• Abilities to understand and the willingness to provide written informed consent;
• ≥ 2 and ≤ 70 years old;
• Recurrent or refractory diffuse midline glioma or diffuse intrinsic pontine glioma patients with confirmed H3K27M mutation and documented lesions. Patients have received standard care of medication, such as gross total resection with concurrent radio-chemotherapy (~54 - 60 Gy, TMZ). Patients must either not be receiving dexamethasone or receiving ≤ 4 mg/day at the time of leukopheresis;
• Karnofsky performance score (KPS) ≥ 60;
• Life expectancy >3 months;
• Satisfactory bone marrow, liver and kidney functions as defined by the following: absolute neutrophile count ≥ 1500/mm^3; hemoglobin > 10 g/dL; platelets > 100000 /mm^3; Bilirubin < 1.5×ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5×ULN; creatinine < 1.5×ULN;
• Peripheral blood absolute lymphocyte count must be above 0.8×10^9/L;
• Satisfactory heart functions;
• Must be willing to follow the instructions of doctors; Women of reproductive potential (between 15 and 49 years old) must have a negative pregnancy test within 7 days of study start. Male and female patients of reproductive potential must agree to use birth control during the study and 3 months post study.

Exclusion criteria

• A prior history of gliadel implantation 4 weeks before this study start or currently receiving antibody based therapies;
• HIV positive;
• Tuberculosis infection not under control;
• History of autoimmune disease, or other diseases require long-term administration of steroids or immunosuppressive therapies;
• History of allergic disease, or allergy to immune cells or study product;
• Patients already actively enrolled in other immune cell clinical study; Patients, in the opinion of investigators, may not be eligible or not able to comply with the study.