This is an open label, non-randomized, single site Phase I study to test the manufacturing feasibility and safety of locoregional (LR) administration of B7-H3CART into the central nervous system of adult subjects with recurrent IDH wild-type GBM using a standard 3+3 dose escalation design.

Inclusion Criteria:

• Histologically confirmed high grade (WHO Grade IV) glioma including but not limited to glioblastoma, gliosarcoma, glioblastoma with oligodendroglial features, glioblastoma with PNET features, tested as IDH wild-type, as per revised WHO 2021 criteria. Patients must also have evidence of tumor recurrence/progression by MRI (RANO criteria) after standard front-line therapy. b. First recurrence or progressive disease after a standard line therapy.

• Resectable disease: Resection is being considered as part of the standard of care for the patient and it is thought that it is feasible that a majority of contrast-enhancing tumor mass/signal can be resected.

• Patients must be between the ages of 18 and 75 years old (inclusive).

• Karnofsky Performance score ≥ 60.

• Use of steroids must be limited to ≤ 4 mg of decadron daily.

• Adequate organ function at time of screening visit including:

  1. Hgb ≥ 12 g/dL (male) or ≥ 11.5 g/dL (females)
  2. ANC ≥ 1500/uL
  3. Platelets ≥ 100,000/uL
  4. Absolute lymphocyte count ≥150/uL
  5. Serum Creatinine ≤ 1.5mg/dl; Cr clearance should be ≥ 50 mL/min
  6. Serum AST and ALT ≤ 3x ULN (Grade 1)
  7. Total Bilirubin ≤ 1.5 X ULN
  8. PT or PTT ≤ 1.25 X ULN
  9. Cardiac ejection fraction ≥45% without signs of physiologically significant pericardial effusion or clinically significant ECG findings.
  10. Baseline oxygen saturation > 92% on room air

• Subjects of child-bearing or child-fathering potential must be willing to use an effective method of contraception (hormonal or two barrier methods) while on study and for at least 4 months following the last CAR T cell infusion or as long as B7-H3CART are detectable in peripheral blood or CSF.

• All female subjects of childbearing age must have a negative blood or urine pregnancy test.

• Ability to understand and willingness to sign a written informed consent document.

• Must be willing and able to comply with procedures, return visits and evaluations at Stanford Health Care while on this protocol.

• Prior Therapy:

  • At least 6 weeks following completion of front-line radiation therapy.
  • At least 3 weeks post chemotherapy or 5 half-lives, whichever is shorter must have elapsed since any prior systemic therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives.
  • At least 4 weeks from bevacizumab treatment, which can be used only for radiation necrosis or pseudo-progression.
  • Prior cytotoxic chemotherapy, radiation, or other anticancer therapies including investigational agents discontinued at least 4 weeks prior to Day 1 of treatment.
  • Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia).

Exclusion Criteria:

• Pregnant or patients who are breastfeeding.
• Prior or concurrent treatment with Avastin (bevacizumab) for the purposes of recurrent disease. Avastin (bevacizumab) may have been used for radiation necrosis.
• Prior exposure to chimeric antigen receptor (CAR) based therapies.
• Known sensitivity or allergy to any agents/reagents used in this study.
• Requires current anticoagulation therapy that cannot be safely paused for surgical resection and Ommaya access.
• Prior malignancy except previously diagnosed and definitively treated more than 3 years prior to trial or whose prognosis is deemed good enough to not warrant surveillance.
• Clinical evidence of significant increased intracranial pressure (i.e. impending herniation) or uncontrolled seizures.
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
• Known history of infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
• Primary immunodeficiency or history of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
• Significant medical diseases or conditions, including poorly controlled conditions: i.e. hypertension, cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory disorders, immunodeficiency (e.g., HIV infection), immune compromised for reasons other than malignancy (e.g., chronic corticosteroid therapy or other immunosuppressive therapy), renal failure including patients requiring dialysis, liver dysfunction, second malignancy (except treated basal cell or localized squamous cell skin carcinomas), or active infection.
• History of bone marrow or stem cell transplantation.
• In the investigator's judgment, the subject is unlikely to complete all protocol- required study visits or procedures, including follow-up visits, or comply with the study requirements for participation.