This phase I trial investigates the side effects of brain tumor-specific immune cells (IL13Ralpha2-CAR T cells) in treating patients with leptomeningeal disease from glioblastoma, ependymoma, or medulloblastoma. Immune cells are part of the immune system and help the body fight infections and other diseases. Immune cells can be engineered to destroy brain tumor cells in the laboratory. IL13Ralpha2-CAR T cells is brain tumor specific and can enter and express its genes in immune cells. Giving IL13Ralpha2-CAR T cells may better recognize and destroy brain tumor cells in patients with leptomeningeal disease from glioblastoma, ependymoma or medulloblastoma.
PRIMARY OBJECTIVES: I. Examine and describe the safety and feasibility of IL13Ralpha2-specific hinge-optimized 41BB-co-stimulatory CAR truncated CD19-expressing autologous T-lymphocytes (IL13Ralpha2-CAR T cells) through intracerebroventricular (ICV) delivery as adjuvant therapy in participants with: Ia. IL13Ralpha2+ leptomeningeal disease from glioblastoma (arm 1). Ib. IL13Ralpha2+ leptomeningeal disease from ependymoma or medulloblastoma (arm 2). II. Determine the activity of IL13Ralpha2-CAR T cells based on survival rate at 3 months for both arms. SECONDARY OBJECTIVES: I. Describe persistence, expansion and phenotype of endogenous and IL13Ralpha2-CAR CAR T cells in peripheral blood (PB), tumor cyst fluid (TCF) and cerebral spinal fluid (CSF), when available. II. Describe cytokine levels in PB, TCF, and CSF (when available) over the study period for each arm. III. Estimate the rate of disease response by Response Assessment in Neuro-Oncology Leptomeningeal Metastases (RANO LM) criteria by study arm where an active response is defined as stable disease or better. IV. Estimate rate of progression free survival at 3 months by study arm. V. Estimate rate of overall survival (OS) at 3 months by study arm. VI. In study participants who undergo post therapy biopsy/resection or autopsy: VIa. Evaluate IL13Ralpha2-CAR T cell persistence in the tumor tissue and the location of the IL13Ralpha2-CAR T cells with respect to the infusion site. VIb. Evaluate IL13Ralpha2 antigen on tumor tissue pre- and post-CAR T cell therapy. VII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment. OUTLINE: Patients receive IL13Ralpha2-CAR T cells ICV over 5 minutes on day 1. Treatment repeats every 7 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles per the discretion of the principal investigator. After completion of study treatment, patients are followed up at 30 days, months 3, 6, 9, 12, and then yearly for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
City of Hope Medical Center
Duarte, California, United States
Incidence of adverse events
Will be assessed using the NCI's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Up to 15 years
Overall survival
The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.
Time frame: At 3 months
CAR T cell detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Measured by absolute number per ul by flow.
Time frame: Up to 4 cycles (4 weeks)
Endogenous T cell levels detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Measured by absolute number per ul by flow.
Time frame: Up to 4 cycles (4 weeks)
Cell phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF)
Measured by absolute number per ul by flow.
Time frame: Up to 4 cycles (4 weeks)
Cytokine levels in PB, TCF and CSF
Time frame: Up to 4 cycles (4 weeks)
Disease response
Measured by Response Assessment in Neuro-Oncology Criteria (RANO LM).
Time frame: Up to 15 years
Time to progression
Progression defined by RANO LM criteria.
Time frame: Up to 15 years
Overall survival
Time frame: Up to 15 years
CAR T and endogenous cells detected in tumor tissue
Detected in tumor tissue by immunohistochemistry (IHC).
Time frame: Baseline
IL13Ralpha2 antigen expression levels in tumor tissue
Measured through the pathology H-score.
Time frame: Baseline
Biomathematical modeling of tumor growth
Will assess tumor growth parameter based on serial brain magnetic resonance imaging (MRI)s. Tumor volumes will be computed for each MRI study beginning with the pre-surgical MRI and will be used to compute growth rates, measured as change in tumor volume over time. Tumor volumes will be derived from T1- and T2-weighted MRI sequences. Growth rates will be compared prior to, during, and following CAR T-cell treatment for 1) each individual patient and 2) averaged for each dose level.
Time frame: Up to 15 years
Biomathematical modeling of perfusion/diffusion
Will assess perfusion/ diffusion parameter based on serial brain magnetic resonance imaging (MRI)s. Perfusion and diffusion analysis will include the blood plasma-tissue rate transfer constant (Ktrans), cerebral blood volume (vp), contrast accumulation rate (lambda), and the apparent diffusion coefficient (ADC). Perfusion/diffusion analysis will be derived from T1-weighted dynamic contrast enhancement (DCE), T2-weighted dynamic susceptibility (DSC), and diffusion weighted imaging (DWI) sequences. The mean value of the perfusion/diffusion parameters from the contrast enhancing lesion volume will be extracted for each MRI study.
Time frame: Up to 15 years
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