Locoregional Administration of Genetically Engineered Cells (EGFR/IL13Rα2 Pool-CAR T Cells) for the Treatment of Recurrent or Progressive High-Grade Gliomas

Summary

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.

Detailed Description

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.

Eligibility Criteria

Interventions