This phase I trial studies the side effects and best dose of chimeric antigen receptor (CAR) T cells with a chlorotoxin tumor-targeting domain in treating patients with MPP2+ glioblastoma that has come back (recurrent) or that is growing, spreading, or getting worse (progressive). Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells.
PRIMARY OBJECTIVES: I. Assess the feasibility and safety of dual delivery of chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs (chlorotoxin \[CLTX\]-CAR T cells) for participants with MMP2+ recurrent or progressive glioblastoma. II. Determine the maximum tolerated dose schedule (MTD) and a recommended phase 2 dosing plan (RP2D) for dual delivery of CLTX-CAR T cells for participants with MMP2+ recurrent or progressive glioblastoma. SECONDARY OBJECTIVES: I. Describe persistence, expansion, and phenotype of endogenous and CLTX-CAR CAR T cells in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF). II. Describe cytokine levels in PB, TCF, and CSF over the study period. III. In research participants who receive the full schedule of 3 cycles of CLTX-CAR T cells: IIIa. Estimate the six month progression free survival (PFS) rate. IIIb. Estimate the nine month overall survival (OS) rate. IIIc. Estimate disease response rates. IIId. Estimate median overall survival (OS). IV. In study participants who undergo an additional biopsy/resection or autopsy: IVa. Evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T cells with respect to the injection site. IVb. Evaluate CLTX-targeted antigen expression levels on tumor tissue pre and post CAR T cell therapy. V. Use mathematical modeling of tumor growth to evaluate benefit of treatment. OUTLINE: This is a dose-escalation study. Patients receive chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes NCI SYs via dual delivery starting on day 0 for 3 weekly cycles over 28 days. Each treatment cycle begins with one or two CAR T cell infusions (one at each catheter site) and lasts for 1 week. Beginning 1 week after cycle 3, patients may continue with CAR T treatment per principal investigator and patient discretion. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 3, 6, 9, and 12 months, and then yearly for up to 15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
19
Given via ICT delivery
Given via ICT/ICV dual delivery
City of Hope Medical Center
Duarte, California, United States
Dose limiting toxicity (DLT)
Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5.0). Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants experiencing DLTs at the recommended phase 2 dose schedule. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity, and arm. 2. Cytokine Release Syndrome (CRS) 3. All other toxicities.
Time frame: 28 days
Chimeric antigen receptor (CAR) T cell
Will assess its levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebrospinal fluid (CSF) (absolute number per ul by flowcytometry). Statistical and graphical methods will be used.
Time frame: 15 years
Endogenous T cell
Will assess its level and phenotype detected in TCF, PB, and CSF (absolute number per ul by flowcytometry). Statistical and graphical methods will be used.
Time frame: 15 years
Cytokine levels in TCF, PB and CSF
Time frame: 15 years
Progression free survival time
Time frame: At 6 months
Disease response
Will be assessed by modified Response Assessment in Neuro-Oncology Criteria (RANO) criteria with the need for bevacizumab as an additional indicator of progression.
Time frame: At 6 months
Overall survival (OS)
Kaplan Meier methods will be used to estimate median OS and graph the results.
Time frame: At 9 months
CAR T cells detected in tumor tissue
Will be assessed by immunohistochemistry.
Time frame: 15 years
Chlorotoxin-targeted antigen expression levels in tumor tissue
Will assess the pathology H score.
Time frame: 15 years
Biomathematical modeling of tumor growth
Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.
Time frame: 15 years
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