This phase I trial studies the side effects and best dose of genetically modified T-cell immunotherapy in treating patients with malignant glioma that has come back (recurrent) or has not responded to therapy (refractory). A T cell is a type of immune cell that can recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and a modified gene is placed into them in the laboratory and this may help them recognize and kill glioma cells. Genetically modified T-cells may also help the body build an immune response against the tumor cells.

PRIMARY OBJECTIVES:

I. Assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded autologous memory-enriched T cells (Arms 1, 2, 3, or 4 = Tcm or Arm 5 = Tn/mem) that are genetically modified using a self-inactivating (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13Ra2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated CD19 (CD19t) for participants with recurrent/refractory malignant glioma in one of the following ways: (1) directly into the tumor (intratumoral), (2) into the tumor cavity (intracavitary), (3) into the lateral ventricles (intraventricular), or (4) into both the tumor/tumor cavity (intratumoral) and into the lateral ventricles (intraventricular) (dual delivery).

II. Determine maximum tolerated dose schedule (MTD)/maximum feasible dose schedule (MFD) and a recommended phase II dosing plan (RP2D) for each arm based on dose limiting toxicities (DLTs) and the full toxicity profile.

SECONDARY OBJECTIVES:

I. In research participants who receive the full schedule of three CAR+ T cell doses:

• Estimate disease response rates,
• Estimate median overall survival, and
• Estimate the mean change from baseline in quality of life using the EORTC QLQ-C30 during and post treatment;

II. Describe cytokine levels (tumor cavity fluid, CSF, peripheral blood) over the study period.

III. Describe CAR T cell and endogenous immune populations (CSF, tumor cavity fluid, peripheral blood) over the study period; and IV. Identify tumor and tumor micro-environment markers associated with response to CAR T cells.

EXPLORATORY OBJECTIVES:

I. Assess the timing and extent of brain inflammation following CAR T cell administration; II. Evaluate CAR T cell product characteristics; and

III. For research participants who undergo a second resection or autopsy:

• Evaluate CAR T cell persistence in the tumor micro-environment and the location of the CAR T cells with respect to the injection, and
• Evaluate IL13Rα2 antigen expression levels pre and post CAR T cell therapy.

OUTLINE: This is a dose-escalation study. Research subjects will receive an initial low dose (cycle 1) followed by 2 additional infusions at a higher cell dose (cycles 2 and 3) of autologous IL13Ra2-CAR/CD19t+ Tcm or Tn/mem, potentially followed by additional cycles at up to the highest tolerated cell dose (cycles 4+). CAR T cells will be administered in one of four ways:

ARM 1: (Intratumoral delivery a/f biopsy): Patients receive IL13Ra2-CAR/CD19t+ Tcm directly into the tumor via intratumoral (ICTb) catheter. Patients who progress on intratumoral administration may move to intraventricular catheter for the optional infusions.

ARM 2: (Intratumoral delivery a/f biopsy/Intracavitary a/f resection): Patients receive IL13Ra2-CAR/CD19t+ Tcm directly into the tumor via intratumoral (ICTb) catheter, or into the tumor resection cavity via intracavitary (ICTr) catheter. Patients who progress on intratumoral/intracavitary administration may move to intraventricular catheter for the optional infusions.

ARM 3: (Intraventricular delivery): Patients receive IL13Ra2-CAR/CD19t+ Tcm via intraventricular (ICV) catheter.

ARM 4: (Dual delivery): Patients receive IL13Ra2-CAR/CD19t+ Tcm via ICTb/r catheter and ICV catheter. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

ARM 5: (Dual delivery): Patients receive IL13Ra2-CAR/CD19t+ Tn/mem via ICTb/r catheter and ICV catheter. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).

CAR T cells will be administered at one of three dose schedules:

• Dose Schedule 1: Cycle 1 - 2x106 CAR T cells, Cycle 2 & 3 - 10x106 CAR T cells, Total dose - 22x106 CAR T cells; Optional cycles ≤10x106 CAR T cells
• Dose Schedule 2: Cycle 1 - 10x106 CAR T cells, Cycle 2 & 3 - 50x106 CAR T cells, Total dose - 110x106 CAR T cells; Optional cycles ≤50x106 CAR T cells
• Dose Schedule 3: Cycle 1 - 20x106 CAR T cells, Cycle 2 & 3 - 100x106 CAR T cells, Total dose - 220x106 CAR T cells; Optional cycles ≤100x106 CAR T cells

After completion of the study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10, and 12 months, and then yearly for 15 years.

Inclusion Criteria:

• SCREENING INCLUSION CRITERIA

• Participant has a prior histologically-confirmed diagnosis of a grade III or IV glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now has radiographic progression consistent with a grade III or IV malignant glioma (MG) after completing standard therapy

• Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of the initial radiation therapy

• Karnofsky performance status (KPS) >= 60%

• Life expectancy > 4 weeks

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

• City of Hope (COH) Clinical Pathology confirms IL13R alpha 2+ tumor expression by immunohistochemistry (>= 20%, 1+)

• All research participants must have the ability to understand and the willingness to sign a written informed consent

• ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION

• Research participant must not require more than 2 mg three times daily (TID) of dexamethasone on the day of PBMC collection.

• Research participant must have appropriate venous access

• At least 2 weeks must have elapsed since the research participant received his/her last dose of prior chemotherapy or radiation

• ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT

• Creatinine < 1.6 mg/dL

• White blood cell (WBC) > 2,000/dl or

• Absolute neutrophil count (ANC) > 1,000

• Platelets >= 100,000/dl

• International normalized ratio (INR) < 1.3

• Bilirubin < 1.5 mg/dL

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limits of normal

• An interval of at least 12 weeks must have elapsed since the completion of initial radiation therapy

• Wash-out requirements (standard or investigational):

  • At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen
  • At least 23 days since the completion of Temodar and/or 4 weeks for any other non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent treatment was with a targeted agent only, and s/he has recovered from any toxicity of this targeted agent, then a waiting period of only 2 weeks is needed from the last dose and the start of study treatment, with the exception of bevacizumab where a wash out period of at least 4 weeks is required before starting study treatment

• ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION

• Research participant has a released cryopreserved T cell product

• Research participant does not require supplemental oxygen to keep saturation greater than 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are progressive

• Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias

• Research participant does not have a fever exceeding 38.5° Celsius (C); there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren't any indications of meningitis

• Research participant serum total bilirubin does not exceed 2 x normal limit

• Research participant transaminases does not exceed 2 x normal limit

• Research participant serum creatinine =< 1.8 mg/dL

• Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell dose

• Research participant platelet count must be >= 100,000; however, if platelet level is between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is >= 100,000

• Research participants must not require more than 2 mg TID of dexamethasone during T cell therapy

Exclusion Criteria:

• SCREENING EXCLUSION CRITERIA
• Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks
• Research participant requires pressor support and/or has symptomatic cardiac arrhythmias
• Research participant requires dialysis
• Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy
• Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study; a legal guardian may substitute for the research participant
• Research participants with any non-malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it unwise to enter the research participant on protocol shall be ineligible
• Research participants with any other active malignancies
• Research participants being treated for severe infection or who are recovering from major surgery are ineligible until recovery is deemed complete by the investigator
• Research participants with any uncontrolled illness including ongoing or active infection; research participants with known active hepatitis B or C infection; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
• Research participants who have confirmed human immunodeficiency virus (HIV) within 4 weeks of screening