Cellular Adoptive Immunotherapy Using Genetically Modified T-Lymphocytes in Treating Patients With Recurrent or Refractory High-Grade Malignant Glioma
Condition: Brain and Central Nervous System Tumors
MeSH terms: Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: Cellular adoptive immunotherapy may stimulate the immune system in different ways
      and stop cancer cells from growing.

      PURPOSE: This clinical trial is studying the side effects of cellular adoptive immunotherapy
      using genetically modified T-lymphocytes and to see how well it works in treating patients
      with recurrent or refractory high-grade malignant glioma.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo
           expanded autologous CD8-positive T-cell clones genetically modified to express the IL-13
           zetakine chimeric immunoreceptor and the Hy/TK selection/suicide fusion protein in
           patients with recurrent or refractory, high-grade malignant glioma.

      Secondary

        -  To evaluate the antitumor activity of adoptively transferred clones in these patients.

        -  To screen for the development of anti-IL13 zetakine and anti-HyTK immune responses in
           these patients.

        -  To evaluate the efficacy of ganciclovir administration for ablating transferred clones
           in vivo should toxicity be encountered.

      OUTLINE:

        -  Leukapheresis and therapy preparation: Patients undergo leukapheresis to obtain
           peripheral blood mononuclear cells. T-cells isolated from the peripheral blood are then
           genetically modified, hygromycin-resistant cloned, expanded ex vivo, and cryopreserved
           until the first clinical or radiographic evidence of recurrence or progression. Patients
           with documented disease recurrence or progression undergo re-biopsy or re-resection of
           the tumor and placement of a reservoir-access device (Rickham shunt) into the tumor
           resection cavity prior to autologous T-cell clone infusion therapy.

        -  Autologous T-cell clone infusion: Patients receive an infusion of autologous
           antigen-specific CD8+ cytotoxic T-lymphocyte clones over 5-10 minutes on days 1, 3, and
           5 of weeks 1 and 2. Treatment repeats every 3 weeks for a total of 2 courses in the
           absence of disease progression or unacceptable toxicity. Patients achieving tumor
           regression with residual disease by MRI after 4 courses of study therapy may receive up
           to 2 additional courses in the absence of disease progression, unacceptable toxicity, or
           a complete response.

      Patients undergo blood, cerebrospinal fluid, and tissue sample collection periodically for
      correlative studies. Samples are assessed for IL13Rα2 expression levels, susceptibility to
      redirected T-cell effector mechanisms, and other tumor and T-cell activation markers.

      After completion of study treatment, patients will be followed monthly for 3 months, then
      every 3 months for two years, and then annually for at least 15 years.
    

Intervention name(s): therapeutic autologous lymphocytes; gene expression analysis; laboratory biomarker analysis
Intervention type(s): Biological; Genetic; Other
Intervention description(s): Cycles of escalating cell dose infusions up to the target cell dose of 10(8); At the time of excess pathology samples documenting response/relapse; CSF generated at the time of each T-cell dose
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult anaplastic astrocytoma; adult diffuse astrocytoma; adult pilocytic astrocytoma; adult subependymal giant cell astrocytoma; adult anaplastic ependymoma; adult ependymoma; adult myxopapillary ependymoma; adult subependymoma; adult anaplastic oligodendroglioma; adult oligodendroglioma; adult brain stem glioma; adult giant cell glioblastoma; adult glioblastoma; recurrent adult brain tumor; adult gliosarcoma; adult mixed glioma; adult pineal gland astrocytoma