This study will evaluate BCB-276, an investigational B7-H3-targeted Chimeric Antigen Receptor (CAR) T cell therapy, in children and young adults with diffuse intrinsic pontine glioma (DIPG). DIPG is a rare and aggressive brain tumor with limited treatment options. CAR T cell therapy uses a patient's own immune cells that are changed in a laboratory to recognize and attack cancer cells. The purpose of this study is to determine whether BCB-276, when given after completion of standard radiation therapy, is safe and can improve survival for patients with DIPG.

To participate, individuals must be between 1 and 26 years of age when they join the study, have a diagnosis of DIPG, and enroll for treatment within 6 weeks of completing initial radiation therapy. Participants must not have received prior anti-cancer therapy beyond radiation with or without temozolomide prior to joining this study.

BCB-276 is administered intraventricularly (into the fluid around the brain), which requires placement of a catheter for treatment. BCB-276 is given every 2 weeks at a research center over a period of several months (approximately 7-8 months). Participation includes travel to a study site, procedures to support treatment administration, sample collection, and ongoing monitoring for safety and effectiveness, with follow-up visits lasting up to about 2 years.

Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive brainstem tumor that primarily affects children and has limited treatment options. Radiation therapy is the current standard of care and may provide temporary benefit, but new treatment approaches are needed.

This Phase 2 study will evaluate BCB-276, an investigational B7-H3-targeted Chimeric Antigen Receptor (CAR) T cell therapy, in children and young adults with DIPG after completion of initial standard radiation therapy. The study will assess survival, safety, and tumor response. All eligible participants will receive BCB-276, and outcomes will be compared with information from similar individuals with DIPG whose data have been collected in a registry.

To take part in this study, eligible patients must begin participation within 6 weeks after completing radiation therapy and must not have received prior anti-cancer therapy other than radiation with or without temozolomide. Participation includes collection of participant's white blood cells by leukapheresis, manufacturing of BCB-276 from the participant's own immune cells, and placement of a catheter or reservoir to deliver treatment directly into the fluid-filled spaces of the brain.

BCB-276 is given at participating research centers approximately every 2 weeks for a planned course of up to 15 doses over approximately 7-8 months. Study visits include treatment, safety monitoring, MRI scans, laboratory tests, and other assessments. Participants may be followed for up to approximately 2 years from the first BCB-276 treatment, and some follow-up visits may be conducted remotely. Because BCB-276 is investigational, side effects may occur and safety will be closely monitored.

Inclusion Criteria:

• Participants must be aged 1 and ≤ 26 years and weigh ≥10kg.
• Diagnosis of Diffuse Intrinsic Pontine Glioma (DIPG) based on imaging, with or without biopsy confirmation consistent with high-grade glioma or diffuse midline glioma
• Able to tolerate leukapheresis and other study procedures in the opinion of the Investigator.
• Central Nervous System (CNS) reservoir catheter present prior to first dose of study drug.
• Participant must have completed standard radiation therapy within 6 weeks of enrollment for participation.
• Performance Status of ≥ 60; mild to moderate restriction or better. Lansky (under 16 years of age) or Karnofsky (16 years of age or older).
• Adequate organ function and overall clinical status to participate, including stable or improving neurologic symptoms.
• Participants of childbearing/fathering potential must agree to use highly effective contraception from the time of enrollment through 12 months following the last T cell infusion.
• Participants with ventriculoperitoneal (VP) shunts need to have a programable system and be able to tolerate temporary adjustment of the shunt required for study treatment.
• Participant must meet all other health and safety criteria defined in the study protocol.
• Participant and/or authorized legal representative willing to provide consent/assent for study participation, including participation in the 15-year long term follow up period.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Previous tumor-directed therapy or treatment-directed clinical study other than standard radiation with or without temozolamide.
• Evidence of metastatic disease.
• Requirement of high or increasing doses of corticosteroids prior to participation.
• Severe swallowing difficulties or other significant clinical conditions that may interfere with participation.
• Presence of an active malignancy other than DIPG.
• Active or uncontrolled human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection based on protocol-required laboratory testing.
• Pregnant or breastfeeding.
• Presence of any condition that, in the Investigator's opinion, would prohibit the participant from undergoing treatment under this protocol.