This is a phase 1 study for patients with newly diagnosed MGMT unmethylated IDH wild-type glioblastoma utilizing autologous activated T-cells armed with bispecific antibody (EGFR-BATs) that recognize the tumor. The investigators hypothesized that the combination of infusions of EGFR BATs and low-intensity focused ultrasound would induce blood-brain barrier opening and increase the permeability of the adoptive immunotherapy. The investigators will radiolabel the EGFR BATs with 89Zr-oxine for subsequent PET imaging to determine the trafficking and uptake of this approach. There is a concern that several infusions of EGFR BATs before BBB opening could change the immune tumor microenvironment that would not allow a permissive BBB after LIFU. Therefore, Arm A will have two LIFU with BBB opening after the 4th and the 8th infusion, and Arm B will have three LIFU with BBB opening after the 1st, 4th, and 8th infusions. This study will determine the safety and feasibility of the combination of low-intensity focused ultrasound (LIFU) with microbubbles BBB opening and EGFR BATs and the access of the adoptive cell immunotherapy to the tumor microenvironment to inform future studies.
Newly diagnosed supratentorial glioblastoma or gliosarcoma IDH wildtype and MGMT unmethylated that express EGFR (score ≥ 1 by IHC)) and confirmed by UVA pathology review.
Age ≥ 18 and ≤ 70 years at the time of signing informed consent.
Karnofsky Performance Status (KPS) ≥ 70.
Be willing and able to provide written informed consent for the trial.
Patients with a diagnosis of another malignancy within 2 years of being on-study. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or any type of in situ cancer. Patients must not be on any treatment for another malignancy.
Patients undergoing only biopsy (partial resection or greater is required).
Patients with cerebellar or brainstem tumors.
Patients with evidence of leptomeningeal dissemination or subependymal spread on initial MRI.
Sequential
anti-EGFR bispecific-armed T cells
DrugIN PROGRESS
Low-Intensity Focused Ultrasound
DeviceLow-Intensity Focused Ultrasound will be used to open the blood-brain barrier
The safety of this treatment will be evaluated through the number of participants experiencing Grade ≥3 dose-limiting toxicities (DLTs).
The safety will be evaluated by determining the number of participants who experience Grade ≥3 DLTs according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 during EGFR BAT and LIFU BBB opening after RT/TMZ. The scale displays Grades 1 through 5 and refers to the severity of the AE. A higher grade (e.g., 5) represents a worse outcome.
The feasibility of this treatment will be determined by the proportion of participants achieving ≥75% of the recommended EGFR BATs dose
The feasibility of this treatment will be determined by calculating the proportion of participants achieving ≥75% (60 x 10\^9 EGFR BATs) of the recommended Phase II EGFR BAT dose.
Incidence and severity of treatment-emergent adverse events (AEs) based on physical examination, vital signs, laboratory parameters, serum chemistry and hematology
Safety will be quantified using AE counts and severity grading per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Physical examinations, vital signs, and laboratory studies will be recorded.
Brain uptake of 89Zr-oxine-labeled EGFR BATs measured by PET standardized uptake values (SUV) with and without LIFU BBB opening
Three PET imaging scans will be taken to quantify trafficking of labeled EGFR BATs into the GBM microenvironment. PET signal (SUV) will be compared across time points and between LIFU BBB-opened and non-opened regions.
Change from baseline in peripheral immune response markers (CTL cytotoxicity)
Peripheral blood samples will be collected at baseline and at protocol-specified time points after treatment initiation. Immune response will be determined by CTL cytotoxicity. Changes from baseline will be summarized for each patient.
Change from baseline in peripheral immune response markers (IFN-γ ELISpot Counts)
Peripheral blood samples will be collected at baseline and at protocol-specified time points after treatment initiation. Immune responses will be determined by IFN-γ ELISpot Counts (SFU). Changes from baseline will be summarized for each patient.
Change from baseline in peripheral immune response markers (Th1/Th2 serum cytokine concentrations)
Peripheral blood samples will be collected at baseline and at protocol-specified time points after treatment initiation. Immune responses will be determined by Th1/Th2 serum cytokine concentrations. Changes from baseline will be summarized for each patient.
PET-based quantification of 89Zr-oxine-labeled EGFR BAT trafficking across the BBB and into the GBM microenvironment after infusions and Low Intensity Focused Ultrasound (LIFU).
PET imaging will be used to measure radiotracer uptake (SUV) in the brain and tumor regions following infusions of 89Zr-labeled EGFR BATs. PET SUV after the 1st infusion's LIFU will be compared to the PET SUV after the 4th and the 8th infusion's LIFU.
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University of Virginia
Lead sponsor
Focused Ultrasound Foundation
Collaborator
NaviFUS Corporation
Collaborator
