b7-h3 car-t for recurrent or refractory glioblastoma

Conditions: Recurrent Glioblastoma; Refractory Glioblastoma

Summary: this is a randomized, parallel-arm, phase i/ii study to evaluate the safety and efficacy of b7-h3 car-t in between temozolomide cycles comparing to temozolomide alone in treating patients with glioblastoma that has come back or does not respond to the standard treatment. the antigen b7-h3 is highly expressed in glioblastoma of a subset of patients. b7-h3 car-t, made from isolated patient peripheral blood mononuclear cells, can specifically attack patient glioblastoma cells that expressing b7-h3.

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 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.

Eligibility criteria:
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 \ 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)