CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII
Condition: Malignant Glioma; Glioblastoma; Brain Cancer; Gliosarcoma
MeSH terms: Glioblastoma; Glioma; Gliosarcoma; Brain Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for
      treating patients with gliomas that involves taking white blood cells from the patient,
      growing them in the laboratory in large numbers, genetically modifying these specific cells
      with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells
      back to the patient. This type of therapy is called gene transfer. In this protocol, we are
      modifying the patient's white blood cells with a retrovirus that has the gene for epidermal
      growth factor receptor (EGFR) vIII incorporated in the retrovirus.

      Objective:

      The purpose of this study is to determine a safe number of these cells to infuse and to see
      if these particular tumor-fighting cells (anti-EGFRvIII cells) are a safe and effective
      treatment for advanced gliomas.

      Eligibility:

      - Adults age 18-70 with malignant glioma expressing the EGFRvIII molecule.

      Design:

      Work up stage: Patients will be seen as an outpatient at the National Institutes of Health
      (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab
      tests, and other tests as needed

      Leukapheresis: If the patients meet all of the requirements for the study they will undergo
      leukapheresis to obtain white blood cells to make the anti-EGFRvIII cells. {Leukapheresis is
      a common procedure, which removes only the white blood cells from the patient.}

      Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
      conditioning chemotherapy, the anti-EGFRvIII cells, and aldesleukin. They will stay in the
      hospital for about 4 weeks for the treatment.

      Follow up: Patients will return to the clinic for a physical exam, review of side effects,
      lab tests, and scans every month for the first year, and then every 1-2 months as long as
      their tumors are shrinking. Follow up visits will take up to 2 days.
    

Detailed description: 
      BACKGROUND:

      - Patients with recurrent gliomas have very limited treatment options. Epidermal growth
      factor receptor (EGFR).

      (EGFRvIII) is the most common mutant variant of EGFR and is present in 24-67% of patients
      with glioblastoma.

        -  EGFRvIII expression promotes oncogenesis and is associated with poor prognosis.

        -  EGFRvIII is not expressed in normal tissue and is an attractive target for
           immunotherapy.

        -  We have constructed a retroviral vector that contains a chimeric antigen receptor (CAR)
           that recognizes the EGFRvIII tumor antigen, which can be used to mediate genetic
           transfer of this CAR with high efficiency without the need to perform any selection.

      OBJECTIVES:

      Primary Objectives

        -  To evaluate the safety of the administration of anti-EGFRvIII CAR engineered peripheral
           blood lymphocytes in patients receiving the non-myeloablative, lymphodepleting
           preparative regimen and aldesleukin.

        -  Determine the six month progression free survival of patients receiving anti-EGFRvIII
           CAR-engineered peripheral blood lymphocytes and aldesleukin following a
           nonmyeloablative, lymphodepleting preparative regimen.

      ELIGIBILITY:

        -  Histologically proven glioblastoma or gliosarcoma expressing EGFRvIII as determined by
           immunohistochemistry (IHC) or Reverse transcription polymerase chain reaction (RT-PCR)

        -  Failed prior standard treatment with radiotherapy with or without chemotherapy

        -  Karnofsky performance score (KPS) greater than or equal to 60

        -  Cardiac, pulmonary and laboratory parameters within acceptable limits

      DESIGN:

        -  The study will be conducted using a Phase I/II design.

        -  Patients will receive a non-myeloablative, lymphodepleting preparative regimen
           consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
           vivo tumorreactive, CAR gene-transduced peripheral blood mononuclear cells (PBMC), plus
           intravenous (IV) aldesleukin.

        -  Once the maximum tolerated cell dose (MTD) has been determined, the study will proceed
           to the phase II portion.

        -  In the phase II portion of the trial, patients will be accrued to two cohorts:

             -  Patients with recurrent malignant glioma receiving steroids at the time of
                treatment.

             -  Patients with recurrent malignant glioma not receiving steroids at the time of
                treatment.

        -  A total of 107 patients may be enrolled over a period of 7 years.
    

Intervention name(s): Epidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL; Aldesleukin; Fludarabine; Cyclophosphamide
Intervention type(s): Biological; Drug; Drug; Drug
Intervention description(s): Day 0: Cells will be infused intravenously over 20-30 minutes. Patients will receive two cell doses, 2 hours apart.; Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).; Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr.
Other intervention name(s): Proleukin; Fludara; Cytoxan
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Mitogens
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cell Therapy; Gene Therapy; Immunotherapy; Brain Cancer; Glioma; Glioblastoma