This phase I trial studies the side effects and best dose of EGFR/IL13Rα2 pool-chimeric antigen receptor (CAR) T cells when given through a thin, flexible tube into the brain (locoregional administration) in treating patients with high-grade gliomas that have come back after a period of improvement (recurrent) or that are growing, spreading, or getting worse (progressive). EGFR/IL13Rα2 pool-CAR T cells are a type of CAR T cell therapy. 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. Then the gene for a special receptor that binds to a certain protein on the patient's tumor cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers.

PRIMARY OBJECTIVE:

I. Assess the safety and determine the maximum tolerated dose (MTD) of locoregional administration of autologous anti-EGFR/anti-IL13Rα2 CAR T-cells (EGFR/IL13Rα2 pool-CAR T cell) therapy.

SECONDARY OBJECTIVES:

I. In participants who receive at least 50% of the assigned cell dose for each cycle (1-4) and at least 70% of the total cumulative dose:

1. Estimate disease control rate (DCR: complete response [CR] + partial response [PR] +stable disease [SD]);
2. Estimate overall response rate (ORR: CR+PR);
3. Estimate time to progression (TTP);
4. Estimate median overall survival, and;
5. Estimate overall survival (OS) at 12-months.

II. Determine feasibility of locoregionally administered EGFR/IL13Rα2 pool-CAR T cell therapy as assessed by leukapheresis and manufacturing processes, including ability to meet the EGFR/IL13Rα2 pool-CAR T cell dose and product release requirements.

EXPLORATORY OBJECTIVES:

I. Describe cytokine levels in cerebrospinal fluid (CSF), tumor cavity fluid (TCF), and peripheral blood (PB) over the study period and changes in the presence of cytokines with respect to observed adverse events and treatment outcomes.

II. Describe CAR T cell and endogenous immune cell populations (CSF, TCF, PB).

III. Describe tumor and tumor microenvironment markers and their relationship to treatment outcomes.

IV. Describe potential on-target, off-tumor impact of infused EGFR/IL13Rα2 pool-CAR T cells via the evaluation of testosterone levels.

V. For participants who undergo secondary resection(s), biopsy(s), or /post-mortem collection:

1. Evaluate CAR T cell persistence in the tumor microenvironment and location of the CAR T cells with respect to the injection site;
2. Evaluate changes in IL13Rα2 antigen expression levels and epidermal growth factor receptor (EGFR) gene alterations in pre and post CAR T cell therapy, and;
3. Evaluate changes in tumor and immune landscape post-therapy.

VI. Descriptively compare IL13Ra2-CAR T cell and EGFR-CAR T cell persistence and expansion dynamics in the CSF and the blood.

VII. Through the use of biomathematical modeling techniques, characterize tumor growth and its relationship to treatment outcomes.

VIII. Evaluate CAR T cell product characteristics.

IX. Assess immune responses directed against EGFR/IL13Rα2 pool-CAR T cells at post-infusion time points.

OUTLINE: This is a dose-escalation study.

Patients undergo leukapheresis followed by surgical resection, biopsy, and intracranial tumoral (ICT) and/or intracranial ventricular (ICV) catheter placement 1-3 weeks prior to cycle 1, day 0. Patients then receive EGFR/IL13Rα2 pool-CAR T cells via ICT and/or ICV catheter over 5 minutes on day 1 of each cycle. Cycles repeat every 7 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of EGFR/IL13Rα2 pool-CAR T cells per principal investigator (PI) and patient discretion and/or undergo additional leukapheresis as needed on study. Patients also undergo echocardiography (ECHO) during screening, as well as fludeoxyglucose (FDG)-positron emission tomography (PET), magnetic resonance imaging (MRI), and blood, TCF, and CSF sample collection throughout the study.

After completion of study treatment, patients are followed up at day 30, months 3, 6, 9, and 12, and then yearly for up to 15 years post last CAR T cell infusion.

Main Inclusion Criteria

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

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with Study PI approval.

• Age 18 years and older.

• KPS ≥ 70%, ECOG ≤ 2 (Appendix A).

• Life expectancy ≥ 4 weeks.

• Participant has a prior histologically confirmed diagnosis of a glioblastoma (IDH-wildtype) or grade 4 IDH-mutant astrocytoma, or has a prior histologically confirmed diagnosis of a grade 2 or 3 astrocytoma and now has radiographic progression consistent with grade 4 IDH-mutant astrocytoma.

• Relapsed disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy (such as temozolomide with or without Optune device), and ≥ 12 weeks after completion of front-line radiation therapy.

• COH Clinical Pathology assessment at the initial tumor presentation or recurrent disease (reference Appendix B):

  • IL13Rα2+ expression by IHC > 20, and
  • EGFR gene-altered by NGS or FISH analysis

• No known contraindications to leukapheresis, steroids, imaging studies, or tocilizumab.

• WBC > 2000 /dl (or ANC ≥ 1,000/mm3)

• Platelets ≥ 75,000/mm3

• Hemoglobin > 9g/dL

• Total bilirubin ≤ 1.5x ULN

• AST ≤ 2.5x ULN

• ALT ≤ 2.5x ULN

• Serum creatinine ≤1.6 mg/dL

• O2 saturation ≥ 95% on room air.

• Seronegative for HIV Ag/Ab combo, HCV, and active HBV

• 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 for the course of the study through at least 3 months after the last dose of CAR T cells.

Main 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.
• Participant has received any live vaccine within 30 days prior to enrollment.
• 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 IV antibiotics (for example, minor scalp infection is not exclusion).
• 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).