Clinical Trial Finder

Inclusion Criteria:

• - Documented informed consent of the participant and/or legally authorized representative.

• - Histologically confirmed diagnosis of World Health Organization (WHO) classification grade IV glioblastoma (GBM).

• - Clinical Pathology confirms B7-H3 positive tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score >= 50).

• - Relapsed/refractory disease confirmed by radiographic evidence after standard therapy.

• - Suitable for the surgery of the placement of the Ommaya catheter.

• - Eastern Cooperative Oncology Group (ECOG) =0 or 1 (need to be confirmed before intratumoral or intracerebroventricular injection) - >= 8 weeks after completion of front-line radiation therapy.

• - >= 6 weeks after completion of nitrourea chemotherapy.

• - >= 14 days after completion of Temozolomide or other chemotherapy.

• - 2 weeks of wash-out time after completion of targeted therapy with related adverse events (AE) on baseline (4 weeks for Bevacizumab).

Patients with other chronic AEs are in the investigator's judgement.

• - Blood cell count： White blood count (WBC) >= 2000/μL；Neutrophil count >= 1500/μL；Platelets >= 100 x 103/μL；Hemoglobin >= 9.0 g/dL.

• - Serum Creatinine <= 1.5×ULN or Creatinine Clearance Rate (Cockcroft and Gault) > 30 mL/min/1.73 m2.

• - Alanine Transaminase (ALT) <= 5×ULN and total bilirubin < 2.0mg/dL.

• - Lung function: Oxygen (O2) saturation >= 92% on room air and < CTCAE grade 1 dyspnea.

• - Heart function: Left ventricular ejection fraction (LVEF) >= 40% by multigated acquisition (MUGA) scan or echocardiogram.

• - Normal coagulation function: prothrombin time (PT)，activated partial thromboplastin time (APTT) and international normalized ratio (INR) - Good blood vessel condition for leukapheresis.

• - Women of childbearing potential (WOCBP): negative urine or serum pregnancy test.

• - Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity within one year after B7-H3 CAR-T infusion.

Exclusion Criteria:

• - Other active malignancy in the past 2 years except non-melanoma skin cancer, completely surgical removed low grade tumor, post-therapeutic limited-stage prostate cancer, biopsy confirmed in situ cervical carcinoma, PAP test confirmed squamous intraepithelial lesions.

• - Participant is undergoing or planning to take other anti-tumor therapies.

• - Participant is systematic steroid-dependent, or is expecting to be treated with systematic steroid.

• - Active immunodeficiency virus (HIV) or hepatitis B or hepatitis C virus infection.

• - Active infection from fungi, bacteria and/or viruses.

• - Known history of the following cardiac diseases in the past 6 months: New York Heart Association (NYHA) defined grade III or IV heart failure, cardiac angioplasty, myocardial infarction, unstable angina and other clinically significant heart diseases.

• - Known history and/or clinically evident central nerve system diseases: seizure, epileptic seizure, aphasia, paralysis, stroke, severe brain damage, dementia, Parkinson's Disease, cerebellar diseases, organic brain syndrome and psychiatric disorders.

• - Autoimmune diseases.

• - Pregnant or breastfeeding females.

• - Therapeutic doses of corticosteroid within 7 days before leukapheresis or 72 hours before B7-H3 CAR-T infusion.

• - Cytotoxic chemotherapy without lymphocytotoxicity within 1 week before leukapheresis except that the treatment has been stopped for more than 3 half-lives of the drug.

• - Lymphocytotoxic chemotherapy (cyclophosphamide, Ifosfamide and bendamustine) within 2 weeks before leukapheresis.

• - Other clinical trials drugs within 4 weeks before leukapheresis except that the drug has no effect or the disease has progressed, and the treatment has been stopped for more than 3 half-lives of the drug.

• - Radiotherapy within 6 weeks before leukapheresis.

• - Prior trials of CAR-T or other cell therapy.

• - Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures.

- Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Background.

• - B7-H3 is expressed in 70% of patients with glioblastoma.

• - B7-H3 is not expressed in normal tissues especially not in central nervous system.

Therefore, it is an attractive GBM target for CAR-T therapy.

• - The investigators constructed a retroviral vector encoding a chimeric antigen receptor (CAR) targeting B7-H3, which can mediate CAR transfer into patient T cells with high efficiency.

Objectives.

• - To evaluate the safety and tolerability intratumoral/intracerebroventricular injection of B7-H3 CAR-T when used in between Temozolomide cycles.

• - To compare the overall survival (OS) and progression-free survival (PFS) of R/R GBM patients treated with B7-H3 CAR-T in between Temozolomide cycles vs.#46;Temozolomide alone.

• - To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in between Temozolomide cycles.

Design.

• - Experimental group: Patients autologous T cells are activated and transduced with retrovirus containing B7-H3 CAR.

CAR-T cells are expanded ex vivo and infused back to patients via intratumoral or intracerebroventricular injection through an Ommaya catheter. 3 injections of CAR-T are planned at two different doses with 1-2 weeks intervals. The CAR-T injections occur in between Temozolomide (TMZ) cycles. Temozolomide treatment during the cycles of CAR-T injections will be stopped and resumed next cycle. Patients may receive additional CAR-T cycles at the discretion of the principal investigator and oncologist.

• - Control group: Patients will receive regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval.

Arms

Active Comparator: Temozolomide alone

Temozolomide will be given to patients orally every 5 days with 23 days interval. The initial dose is 150 mg/m2 on the first day and 200 mg/m2 for the rest if no toxicity is seen. If 200 mg/m2 is toxic, the drug will return to 150 mg/m2 or will be stopped.

Experimental: Temozolomide + B7-H3 CAR-T

Temozolomide will be given to patients orally every 5 days with 23 days interval. The initial dose is 150 mg/m2 on the first day and 200 mg/m2 for the rest if no toxicity is seen. If 200 mg/m2 is toxic, the drug will return to 150 mg/m2 or will be stopped. The B7-H3 CAR-T will be administrated via intratumoral or Intracerebroventricular injection through an Ommaya catheter in between Temozolomide cycles. Temozolomide treatment in the cycles of B7-H3 CAR-T treatment will be stopped.

Interventions

Drug: - Temozolomide

Temozolomide is an FDA-approved drug that is given to patients

Biological: - B7-H3 CAR-T

B7-H3-targeting CAR-T cells derived from patient own peripheral blood mononuclear cells will be given to patients via intracerebral injection though an Ommaya catheter