The goal of this protocol is to transfer autologous peripheral blood mononuclear cells
(PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes
epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients
with recurrent glioblastoma (GBM) following stereotactic radiosurgery (SRS). The CAR used is
targeted to a tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII,
which is expressed on a subset of patients. Normal PBMCs derived from patients with GBM are
genetically engineered with a viral vector encoding the CAR and infused directly into the
patient's tumor with the aim of mediating regression of their tumors. Despite our CAR being
targeted to a tumor specific antigen, given the prior toxicity using CARs that were not
targeted to tumor-specific antigens, the investigators elected to begin with very low doses
of cells. Enrollment on this study was suspended in April 2020 while an amendment to reduce
the anticipated number of participants was under review and approved. The decision to
terminate the study was made in January, 2021 to shift toward the next iteration of a related
CAR T cell trial.
Patients with evidence of radiographic recurrence who expressed EGFRvIII on their original
tumor diagnosis had autologous PBMCs harvested by leukapheresis. These autologous PBMCs were
transduced with a retrovirus containing the sequences for the EGFRvIII CAR and sent to the
Duke Radiopharmacy for radiolabeling with 111Indium (111In). Within 2-3 weeks of
leukapheresis, on Day -4 to -2, patients had a BrainLab MRI to prepare for biopsy and
catheter placement. On Day -1, the patient underwent standard of care (SOC) stereotactic
biopsy under local anesthesia to confirm tumor recurrence. At the time of biopsy, prior to
catheter insertion and administration of study drug, the presence of recurrent tumor was
confirmed by histopathology. If tumor recurrence was confirmed, a catheter was placed
intratumorally for delivery of EGFRvIII-CARs by Convection Enhanced Delivery (CED).
SRS will took place on Day 0 (+1 day) and 111In-labeled EGFRvIII-CARs were infused on the
same day over a 6 to 6.5 hour period immediately after SRS.
On days 1 and 2 after 111In-labeled EGFRvIII-CAR infusion, whole planar imaging followed by
Single-Photon Emission Computed Tomography (SPECT) Computed Tomography (CT) imaging assessed
the intracerebral and systemic localization of the 111In-labeled EGFRvIII-CARs that described
the distribution of EGFRvIII-CARs within the brain and systemically.
This protocol was designed to determine the maximum tolerated dose (MTD) of a novel,
tumor-specific treatment with autologous EGFRvIII-CARs. The proposed starting dose was 2.5 x
10^8 of 111In-labeled cells in 3 milliliters (mL). The infusion flow rate was fixed at 0.5
Enrollment on this study was suspended in April 2020 while an amendment to reduce the
anticipated number of participants was under review and approved. Upon approval of this
amendment, the enrollment suspension remained due to a change in access to necessary
equipment for CAR manufacturing. The decision to terminate the study was made in January,
2021 to shift toward the next iteration of a related CAR T cell trial. The knowledge gained
from this study experience is directing our next CAR T-cell platform and will be used to
secure additional funding.
1. Disease progression or recurrence of a supratentorial World Health Organization (WHO)
grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with
measurable disease. At the time of biopsy, prior to stereotactic radiosurgery (SRS)
and administration of the EGFRvIII-CARS, the presence of recurrent tumor must be
confirmed by histopathological analysis.
2. Adults ≥ 18 years old.
3. Karnofsky Performance Status (KPS) score ≥ 70.
4. EGFRvIII, the target antigen, must be identified on tumor tissue by
immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR), i.e. EGFRvIII positive
via pathology report.
5. Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥
125,000 cells/µl (prior to biopsy).
6. Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT), and
bilirubin ≤ 1.5 times upper limit of normal (prior to biopsy).
7. Signed informed consent approved by the Institutional Review Board.
8. Female patients must not be pregnant or breast-feeding. Female patients of
childbearing potential (defined as < 2 years after last menstruation or not surgically
sterile) must use a highly effective contraceptive method (allowed methods of birth
control, [i.e. with a failure rate of < 1% per year] are implants, injectables,
combined oral contraceptives, intra-uterine device [IUD; only hormonal], sexual
abstinence or vasectomized partner) during the trial and for a period of > 6 months
following the last administration of trial drug(s). Female patients with an intact
uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy
test within 48 hours prior to starting SRS.
9. Fertile male patients must agree to use a highly effective contraceptive method
(allowed methods of birth control [i.e. with a failure rate of < 1% per year] include
a female partner using implants, injectables, combined oral contraceptives, IUDs [only
hormonal], sexual abstinence or prior vasectomy) during the trial and for a period of
> 6 months following the last administration of trial drugs.
10. Meet eligibility requirements for SRS: able to get MRI; the patient must have a lesion
that, in the opinion of the study radiation oncologist, can safely receive SRS to the
entire tumor; must not be abutting optic apparatus or brainstem and catheter tip will
be at least 5mm away from the ventricle; and must be able to be secured and positioned
in a stereotactic U-frame mask.
1. Pregnant or breast-feeding.
2. Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.
3. Patients who cannot undergo MRI with contrast or SPECT/CT.
4. Patients with evidence of tumor in the brainstem, cerebellum, optic apparatus, or
spinal cord, radiological evidence of actively growing multifocal disease, or
5. Patients < 12 weeks from the end of radiation therapy, unless they have two
progressive scans at least 4 weeks apart, have progression outside of the radiation
field, or have histologic confirmation of progression.
6. Severe, active comorbidity, including any of the following:
1. Unstable angina and/or congestive heart failure requiring hospitalization;
2. Transmural myocardial infarction within the last 6 months;
3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of study initiation;
4. Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy;
5. Known hepatic insufficiency resulting in clinical jaundice and/or coagulation
6. Known autoimmune disorder, such as HIV;
7. Major medical illnesses or psychiatric impairments that, in the investigator's
opinion, will prevent administration or completion of protocol therapy;
8. Active connective tissue disorders, such as lupus or scleroderma that, in the
opinion of the treating physician, may put the patient at high risk for radiation
7. Co-medication that may interfere with study results; e.g. immuno-suppressive agents
other than corticosteroids.
8. Prior, unrelated malignancy requiring current active treatment with the exception of
cervical carcinoma in situ and adequately treated basal cell or squamous cell
carcinoma of the skin;
9. Current, recent (within 4 weeks of the administration of this study agent), or planned
participation in another experimental therapeutic drug study.
10. Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for
nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or
cyclophosphamide (1 week)] prior to biopsy unless patients have recovered from side
effects of such therapy.
11. Patients with an active infection requiring intravenous treatment or having an
unexplained febrile illness (Tmax > 99.5 F, 37.5 C).
12. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to CAR
T Cell infusion.
13. Prior therapy targeted to EGFRvIII.
14. Prior history of brain SRS, (patients who have received external beam radiation per
standard of care are allowed).