CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated main consent is processed. However, the research participant is allowed to proceed with surgery/Rickham placement and CAR T cell infusion only after the translated main consent form is signed
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Age: ≥ 18 years
* Karnofsky performance status (KPS) ≥ 70%, Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Life expectancy ≥ 4 weeks
* If the participant has a shunt, they must be informed of the following:

  * If the shunt is not programmable, the participant must be willing to have a programmable shunt placed prior to CAR T cell infusion, and
  * If the shunt is programmable, in order to proceed to the treatment portion of the study, the participant must be able to tolerate their shunt being functionally closed for at least 2 hours
* Participant has a prior histologically-confirmed diagnosis of a grade 3 or 4 IDH-mutant astrocytoma or glioblastoma, or has a prior histologically-confirmed diagnosis of a grade 2 or 3 astrocytoma and now has radiographic progression consistent with grade 3 or 4 IDH-mutant astrocytoma
* Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy, and ≥ 12 weeks after completion of front-line radiation therapy
* COH clinical pathology confirms IL13Rα2+ tumor expression by immunohistochemistry (H-score ≥ 80)
* No known contraindications to leukapheresis, steroids, or tocilizumab
* White blood cell (WBC) \> 2000 /dl (or absolute neutrophil count \[ANC\] ≥ 1,000/mm\^3) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Platelets ≥ 75,000/mm\^3 (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Hemoglobin ≥ 8g/dl (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Aspartate aminotransferase (AST) ≤ 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Alanine aminotransferase (ALT) ≤ 2.5 x ULN (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Serum creatinine ≤ 1.6 mg/dL (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Oxygen (O2) saturation ≥ 95% on room air (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Seronegative for HIV antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
* Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (to be performed within 14 days prior to leukapheresis unless otherwise stated)

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Owing to higher frequency of wound-related complications, participants who require active bevacizumab therapy at the time of enrollment are excluded
* Participant has not yet recovered from toxicities of prior therapy
* Uncontrolled seizure activity and/or clinically evident progressive encephalopathy
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* Clinically significant uncontrolled illness
* Active autoimmune disease requiring systemic immunosuppressive therapy
* Active infection requiring intravenous (IV) antibiotics (e.g., minor scalp infection is not an exclusion)
* Known history of human immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
* Other active malignancy. Note: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the investigator's judgment, contraindicate the patient'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)

主要终点：Dose-limiting toxicities (DLTs) · Will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants experiencing DLTs at the maximum tolerated dose schedule · Up to 28 days；Incidence of grade 3+ adverse events (AEs) · Will be assessed using the CTCAE v 5.0. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm. In study participants who received the full schedule of 4 cycles. · Up to 30 days after last dose of study drug；Incidence of cytokine release syndrome · Will be graded using American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Criteria. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm. In study participants who received the full schedule of 4 cycles. · Up to 30 days after last dose of study drug；Incidence of all other AEs · Will be assessed using the CTCAE v 5.0. Neurotoxicity will be graded using ASTCT Consensus Criteria, Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome grading system, and tumor inflammation-associated neurotoxicity grading system. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, attributions, and arm. · Up to 30 days after last dose of study drug
次要终点：Overall response rate；Complete response rate；Overall survival (OS)；Ability to meet the TGFβR2KO/IL13Rα2-CAR T cell dose requirements (product feasibility)；Ability to meet product release requirements (product feasibility)；Maximum feasible dose (MFD)

• Treatment (TGFβR2KO/IL13Rα2 CAR T-cells) · EXPERIMENTAL · Patients undergo leukapheresis and standard of care surgical resection with or without placement of Rickham catheter. Starting on day 0, patients receive autologous TGFβR2KO/IL13Rα2-CAR T cells intracranially over approximately 5 minutes QW. Cycles repeat weekly for up to 4 cycles (28 days) in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles if they continue to meet infusion criteria and have doses available for infusion. Patients also undergo CSF and blood sample collection and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) and MRI throughout the study. Additionally, patients may undergo echocardiography at screening.

This phase I trial tests the safety, side effects and best dose of TGFβR2KO/IL13Rα2 chimeric antigen receptor (CAR) T-cells given within the skull (intracranial) in treating patients with glioblastoma or IDH-mutant grade 3 or 4 astrocytoma that has come back after a period of improvement (recurrent) or that is growing, spreading, or getting worse (progressive). CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack tumor cells. T cells are taken from a patient's blood. When the cells are taken from the patient's own blood, it is known as autologous. Then the gene for special receptors that bind to a certain proteins on the patient's tumor cells are added to the T cells in the laboratory. The special receptors are called CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain tumors. Giving TGFβR2KO/IL13Rα2 CAR T cells may be safe, tolerable, and/or effective in treating patients with recurrent or progressive glioblastoma or grade 3 or 4 IDH-mutant astrocytoma.