Chemotherapy and CAR-T Cell Immunotherapy (Brain Tumor‐Specific Immune Cells) for the Treatment of IL13Ralpha2 Positive Recurrent or Refractory Brain Tumors or Newly Diagnosed DIPG/DMG

Inclusion Criteria

• ENROLLMENT/LEUKAPHERESIS ELIGIBILITY
• Documented informed consent of the participant and/or legally authorized representative. * Assent, when appropriate, will be obtained per institutional guidelines
• Agreement to allow the use of archival tissue from diagnostic tumor biopsies
• Age Criteria: * City of Hope (COH) patients: =< 21 years at the time of initial diagnosis, and age 4 to 24 years at the time of enrollment (leukapheresis) * Children’s Hospital, Los Angeles (CHLA) and University of Michigan patients: =< 21 years at the time of initial diagnosis, and age >1 to 24 years at the time of enrollment (leukapheresis).
• Completed history and physical exam, vital signs, and Karnofsky/Lansky performance status assessment. Performance score >= 60% except for loss of mobility due to disease involvement; e.g., confinement to a wheelchair due to spinal cord compression
• Life expectancy > 4 weeks
• Participant has a prior histologically‐confirmed malignant brain neoplasm confirmed by pathology
• City of Hope (COH) clinical pathology confirms IL13Ralpha2+ tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H‐score >= 50)
• If the participant has a shunt, they must be informed of the following: * If the shunt is not programmable, they 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, they must be able to tolerate their shunt being functionally closed for at least 2 hours
• Platelets >= 50,000/mm^3 (to be performed within 6 weeks of enrollment)
• Total bilirubin =< 2 X upper limit of normal (ULN) (unless has Gilbert’s disease) (to be performed within 6 weeks of enrollment)
• Aspartate transaminase (AST) =< 2 x ULN (to be performed within 6 weeks of enrollment)
• Alanine transferase (ALT) =< 2 x ULN (to be performed within 6 weeks of enrollment)
• Creatinine clearance of >= 75mL/min/1.73m^2 (to be performed within 6 weeks of enrollment)
• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV)* and active HBV (surface antigen negative) (to be performed within 6 weeks of enrollment) *If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed
• Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (to be performed within 6 weeks of enrollment)
• QuantiFERON- tuberculosis (TB) Gold or equivalent * Results do not impact patient eligibility, however the test must be initiated prior to enrollment
• 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 6 months after the last dose of protocol therapy. * Childbearing potential defined as not being surgically sterilized (males and females) or have not been free, once initiated, from menses for > 1 year (females only)
• LEUKAPHERESIS SPECIFIC INCLUSIONS
• Research participant must not require more than 0.1mg/kg/day total dose (0.03mg/kg/dose three times per day, max of 6mg/day) of dexamethasone for three days prior to peripheral blood mononuclear cell (PBMC) collection
• Research participant must have appropriate venous access, or be willing to have a temporary line placed for collection
• At least 2 weeks must have elapsed since the research participant received his/her last dose of prior targeted agents, chemotherapy or radiation
• Research participant must have absolute lymphocyte count (ALC) >= 300 cells/μL within 7 days of leukapheresis
• TREATMENT ELIGIBILITY
• Evidence of definitive radiographic progression after initial therapy (MRI and/or PET images confirmed by radiology) is required to proceed with the treatment portion of the study (as outlined below); participants with DIPG or DMG may be treated prior to disease progression but within 2-16 weeks after completion of standard radiation therapy
• ELIGIBILITY TO PROCEED WITH LYMPHODEPLETION (except for cohort 1)
• Pulmonary: 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
• Cardiac: Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias
• Active infection: Research participant does not have a fever exceeding 38.5 degree celsius; there is an absence of positive blood cultures for bacteria, fungus, or virus within 48‐hours prior to CAR T cell infusion and/or there aren’t any indications of meningitis
• Hepatic: Research participant serum total bilirubin or transaminases does not exceed 2 x normal limit
• Renal: Research participant serum creatinine < 1.8 mg/dL
• Neurologic: Research participant does not have uncontrolled seizure activity following surgery prior to starting lymphodepletion
• Prior to start of lymphodepletion administration, participants must have a suitable CNS access device in place that, per the discretion of the PI, has sufficiently healed
• Karnofsky/Lansky performance score ≥ 60% except for loss of mobility due to disease involvement, e.g., confinement to a wheelchair due to spinal cord compression
• At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen
• At least 14 days since the completion of temozolomide and/or 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
• ELIGIBILITY TO PROCEED WITH EACH CAR T CELL CYCLE
• Research participant has a released cryopreserved CAR T cell product (verified by review of product Certificate of Analysis)
• 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 degree celsius; 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 or transaminases does not exceed 2 x normal limit
• Research participant serum creatinine < 1.8 mg/dL
• Research participant does not have uncontrolled seizure activity
• Research participant platelet count must be >= 50,000. However, if platelet level is between 25,000‐49,000, then T‐cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is >= 50,000
• Research participants must not require more than 0.1 mg/kg/day total dose (0.03 mg/kg/dose three times per day, max of 6mg/day) of dexamethasone during CAR T cell therapy
• If the participant has a shunt, it must be programmable, and the participant must be able to tolerate the shunt being functionally closed for at least 2 hours. If the research participant already has a shunt in place and it’s not programmable, the participant understands that a programmable shunt must be placed prior to CAR T cell infusion
• Karnofsky/Lansky performance score ≥60% except for loss of mobility due to disease involvement, e.g., confinement to a wheelchair due to spinal cord compression (Cycle 1 only)

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 participant with any non‐malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the study team deems it unwise to enter the research participant on protocol shall be ineligible
• Research participant being treated for severe infection or recovering from major surgery is ineligible until recovery is deemed complete by the study team
• Research participant with any other active malignancies
• Research participant with any uncontrolled illness including ongoing or active infection. Research participant with known active hepatitis B or C infection; research participant with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
• Research participant who has confirmed HIV positivity within 4 weeks of enrollment (testing via an HIV Ag/Ab Combo Assay or quantitative polymerase chain reaction [qPCR])
• Females only: Pregnant or breastfeeding
• 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)