Locoregionally Delivered Autologous B7-H3 Chimeric Antigen Receptor T Cells (B7-H3CART) for the Treatment of Recurrent Glioblastoma Multiforme

Inclusion Criteria

• Histologically confirmed high grade (World Health Organization [WHO] grade IV) glioma including but not limited to glioblastoma, gliosarcoma, glioblastoma with oligodendroglial features, glioblastoma with primitive neuroectodermal tumors (PNET) features (as per revised WHO 2021 criteria). * Patients must also have evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) (Response Assessment in Neuro-Oncology [RANO[ criteria) after standard front -line therapy, prior to trial enrollment and surgery. * First recurrence or progressive disease after a standard line therapy. * Tumor documented as IDH wild-type. * Archival tumor tissue block or 20 unstained formalin-fixed paraffin-embedded (FFPE) slides from any prior surgery are available for mutation testing and additional sequencing.
• 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).
• Resectable disease: In the neurosurgeon’s judgement, surgical resection (biopsy, partial resection, or gross total resection) is being considered as part of standard of care and is thought that it is feasible that a majority of contrast- enhancing tumor mass/signal can be resected.
• Age: Between 18 and 75 years old (inclusive).
• Performance Status: Karnofsky score >= 60.
• Use of steroids must be limited to =< 4 mg of decadron per day.
• Contraception: Subjects of child-bearing or child-fathering potential must be willing to u se an effective method of contraception (hormonal or two barrier methods) from the time of enrollment on this study and for at least four (4) months after receiving last dose of B7-H3CART cells or as long as they are detectable in peripheral blood or CSF.
• Hemoglobin (Hgb) >= 12 g/dL (male) or >= 11.5 g/dL (females).
• Absolute neutrophil count (ANC) >= 1500/uL.
• Platelet count >= 100,000/uL.
• Absolute lymphocyte count >= 150/uL.
• Creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min.
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3x upper limit of normal (ULN) (grade 1).
• Total bilirubin =< 1.5x ULN (subjects with Gilbert’s syndrome allowed if direct bilirubin within normal limits).
• Prothrombin time (PT) or partial thromboplastin time (PTT) =< 1.25 X ULN.
• Cardiac ejection fraction >= 45%.
• No evidence of physiologically significant pericardial effusion.
• No clinically significant electrocardiogram (ECG) findings.
• Baseline oxygen saturation > 92% on room air.
• Pregnancy: Females of childbearing potential (defined as women =< 50 years of age, or >50 years of age with a history of amenorrhea for =< 12 months prior to study entry) must have a negative blood or urine pregnancy test.
• Ability to understand and the willingness to personally sign the written Institutional Review Board (IRB)-approved informed consent document.
• Must be willing and able to come to comply with procedures, return visits and evaluations at Stanford Medical Center while on this protocol.

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.
• 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 urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
• Known history of infection with human immunodeficiency virus (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 polymerase chain reaction (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., human immunodeficiency virus [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.