EGFRvIII CAR T Cells for Newly-Diagnosed WHO Grade IV Malignant Glioma
Condition: Glioblastoma; Gliosarcoma
MeSH terms: Glioblastoma; Gliosarcoma
Intervention: EGFRvIII CAR T cells
Intervention description: The name of the drug is CAR gene-modified T cells or abbreviated as EGFRvIII CARs. The class of action is a biological and the mechanism of action is cytotoxicity. The drug substance is autologous T cells transduced with a retroviral vector encoding for a chimeric antigen receptor (CAR) directed against the tumor specific antigen, EGFRvIII. EGFRvIII CARs are genetically engineered T cells that have been taken from patients with GBM ex vivo to express a CAR recognizing the GBM tumor-specific antigen EGFRvIII, which is expressed on a subset of GBMs but not in normal human tissues with the aim of mediating regression of their tumors. Patients' CARs will be radiolabeled with 111In for correlative studies in the expanded cohort.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      Please note that enrollment on this study terminated early due to the end of grant funding.

      Newly diagnosed WHO grade IV malignant glioma subjects who are eligible were enrolled
      following surgery to remove their brain tumor. They then underwent a leukapheresis to harvest
      cells for the generation of the study drug, Epidermal Growth Factor variant III Chimeric
      Antigen Receptor (EGFRvIII CAR) T cells prior to beginning standard of care (SOC) radiation
      therapy (RT) with temozolomide (TMZ). Once SOC RT with TMZ was completed, subjects returned
      for the post-RT brain imaging assessment, and, if stable, started post-RT TMZ cycles.
      Patients received up to 3 cycles of dose-intensified TMZ prior to receiving the EGFRvIII CAR
      T cells, which was infused in dose escalation cohorts. Following a one-month delay between
      cycles, the subject resumed post-RT cycles of TMZ and were monitored with blood work and
      brain imaging as per SOC.

      An expanded cohort of 12 subjects was originally planned for once the maximally tolerated
      dose (MTD) was reached in the dose escalation cohorts, in order to obtain a more precise
      estimate of the probability of unacceptable toxicity and to track the EGFRvIII CAR T cells
      using 111 Indium (111In) labeling. Computed Tomography (CT) was planned on days 1, 2, and 3
      post-infusion to determine intracerebral (IC) localization.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 18-80 years of age

          2. Histopathologically proven newly-diagnosed, supratentorial glioblastoma or gliosarcoma
             (World Health Organization [WHO] Grade IV)

          3. Karnofsky Performance Status (KPS) score ≥ 70

          4. The presence of the target antigen, EGFRvIII, must be identified on tumor tissue by
             immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR).

          5. Hematology:

               -  Absolute Neutrophil Count (ANC) ≥ 1000/mm^3 without the support of filgrastim

               -  Platelet count ≥ 100,000/mm^3

               -  Hemoglobin ≥ 8.0 g/dl (eligibility level for hemoglobin may be reached with
                  transfusion)

          6. Chemistry:

               -  Alanine Amino Transferase (ALT)/Aspartate Amino Transferase (AST) ≤ 2.5 times the
                  upper limit of normal

               -  Creatinine ≤ 1.6 mg/dl

               -  Total bilirubin ≤ 1.5 mg/dl

        Exclusion Criteria:

          1. Patients who are pregnant, breast-feeding, or unwilling to practice an effective
             method of birth control

          2. Patients with known potentially anaphylactic allergic reactions to
             Gadolinium-Diethylene Triamine Pentaacetic Acid (gd-DTPA)

          3. Patients who cannot undergo Magnetic Resonance Imaging (MRI) or Single Photon
             Emission-Computed Tomography (SPECT) due to obesity or to having certain metal in
             their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal
             prostheses, joints, rods, or plates)

          4. Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, or with
             evidence of leptomeningeal disease

          5. Active infection requiring treatment or an unexplained febrile (> 101.5 F) illness

          6. Known autoimmune disease, immunosuppressive disease or human immunodeficiency virus
             (HIV) infection (i.e., known HIV or Hepatitis C)

          7. Patients with unstable or severe intercurrent medical conditions such as severe heart
             or lung disease

          8. Patients with previous history of radiosurgery, brachytherapy, gliadel implantation,
             or radiolabeled monoclonal antibodies

          9. Prior antitumor therapy for glioma (other than steroids)

         10. Allergic to TMZ