IL13Ralpha2-Targeted Chimeric Antigen Receptor (CAR) T Cells with or without Nivolumab and Ipilimumab in Treating Patients with Recurrent or Refractory Glioblastoma

Inclusion Criteria

• 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. If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Ages >= 18 years
• Karnofsky performance status (KPS) >= 60%, Eastern Cooperative Oncology Group (ECOG) =< 2
• Life expectancy >= 4 weeks
• Histologically confirmed diagnosis of World Health Organization (WHO) classification grade IV glioblastoma (GBM), or has a prior histologically-confirmed diagnosis of a grade II or III glioma and now has radiographic progression consistent with a grade IV GBM after completing standard therapy.
• Relapsed/refractory disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy, and >= 12 weeks after completion of front‐line radiation therapy
• City of Hope (COH) Clinical Pathology confirms IL13Ralpha2+ tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H‐score >= 50)
• Participants with a known history of congestive heart failure (CHF) or cardiac symptoms consistent with New York Heart Association (NYHA) classification III-IV within 6 months prior to day 1 of protocol treatment, cardiomyopathy, myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications or with clinical history suggestive of the above must have an electrocardiogram (EKG) and echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatment
• 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)
• Fasting blood glucose within upper limit of normal (ULN) (to be performed within 14 days prior to leukapheresis unless otherwise stated)
• Total bilirubin =< 1.5 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 human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C Ab*, active hepatitis B virus (HBV) (surface antigen negative), hepatitis A virus IgM antibody (to be performed within 14 days prior to leukapheresis unless otherwise stated) * 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 14 days prior to leukapheresis unless otherwise stated)
• 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 5 months after the last dose of nivolumab and/or 3 months after the last cycle of CAR T cells. * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
• CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participant must not require more than 6 mg daily of dexamethasone on the day of PBMC collection
• CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participant must have appropriate venous access or be willing to undergo central catheter line placement
• CRITERIA TO PROCEED WITH PBMC COLLECTION: At least 2 weeks must have elapsed since the research participant received his/her last dose of prior chemotherapy or radiation
• CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participants has signed leukapheresis informed consent
• CRITERIA FOR TREATMENT CONSENT AND ARM ASSIGNMENT/RANDOMIZATION: In the opinion of the clinical PI, the research participant has progressed (e.g., recent MRI indicates progression prior to surgery, etc.)
• CRITERIA FOR TREATMENT CONSENT AND ARM ASSIGNMENT/RANDOMIZATION: In the opinion of the research PI based on communications with the manufacturing team, the research participant’s selected Tn/mem population is sufficient to generate an acceptable CAR T cell product (this will be verified by email correspondence from the manufacturing team to the study team)
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): KPS >= 60%
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Creatinine =< 1.6 mg/dL
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): WBC >= 2,000/dl (or ANC >= 1,000)
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): INR =< 1.3, but may give fresh frozen plasma to bring to 1.3
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Bilirubin =< 1.5 ULN
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): ALT and AST =< 2.5 X upper limits of normal
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Research participants must not require more than =< 6 mg daily of dexamethasone
• CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Washout requirements: * At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen * At least 23 days since the completion of temozolomide 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 * For bevacizumab the wash out period of at least 4 weeks is required before starting study treatment
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: KPS >= 60%
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: Creatinine =< 1.6 mg/dL
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: WBC >= 2,000/dl (or ANC >= 1,000)
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: INR =< 1.3, but may give fresh frozen plasma to bring to 1.3
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: Bilirubin =< 1.5 ULN
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: ALT and AST =< 2.5 X upper limits of normal
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: Second-line radiation therapy (post-leukapheresis) within 4 weeks of surgery/Rickham placement
• CRITERIA TO PROCEED WITH SURGERY/RICKHAM CATHETER PLACEMENT: Washout requirements (required for Arm 2 only): * At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen * At least 23 days since the completion of temozolomide 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 * For bevacizumab the wash out period of at least 4 weeks is required before starting study treatment
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant has a released cryopreserved CAR T cell product
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Participant has completed neoadjuvant therapy (Arm 1 only)
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Participant has undergone Rickham catheter placements
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant does not require supplemental oxygen to keep saturation >= 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are progressive
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant does not have a fever exceeding 38.5 degrees 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
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Serum total bilirubin >= 1.5 x ULN.
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: AST and ALT do not exceed =< 2.5 x ULN
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant’s serum creatinine =< 1.6 mg/dL
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant does not have uncontrolled seizure activity following surgery prior to starting the first T cell cycle
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant platelet count must be >= 100,000. However, if platelet level is between 75,000–99,000, then T-cell infusion may proceed if after platelet transfusion the count is >= 100,000
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: For cycles 1-4: Research participants must not require more than 6 mg daily of dexamethasone during CAR T cell therapy
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: For cycles 5+: Research participants must not require more than 12 mg daily of dexamethasone during CAR T cell therapy
• CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: 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 temozolomide 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

Exclusion Criteria

• Prior CTLA-4, PD‐1 or PD‐L1 inhibitor therapy
• Participant is steroid‐dependent, requiring more than 6 mg of dexamethasone per day at the time of enrollment
• Participant has not yet recovered from toxicities of prior therapy
• History of or active autoimmune disease requiring systemic immunosuppressive treatment
• 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
• Active diarrhea
• Clinically significant uncontrolled illness
• Active infection requiring antibiotics
• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
• Other active malignancy
• Females only: Pregnant or breastfeeding
• 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)