Cellular Adoptive Immunotherapy Using Genetically Modified T-Lymphocytes in Treating Patients With Recurrent or Refractory High-Grade Malignant Glioma

• Feasibility [ Time Frame: 1 year after the end of treatment on study ] [ Designated as safety issue: No ]
  
• Safety [ Time Frame: 1 year after the end of treatment on study ] [ Designated as safety issue: Yes ]
  

• Anti-tumor activity of adoptively transferred clones [ Time Frame: 1 year after the end of treatment on study ] [ Designated as safety issue: No ]
  
• Anti-IL 13 zetakine and anti-HyTK immune response in patients [ Time Frame: 1 year after the end of treatment on study ] [ Designated as safety issue: Yes ]
  
• Efficacy of ganciclovir for clone ablation (in the event of toxicity) [ Time Frame: 1 year after the end of treatment on study ] [ Designated as safety issue: Yes ]
  

Biological: therapeutic autologous lymphocytes
Cycles of escalating cell dose infusions up to the target cell dose of 10(8)
Genetic: gene expression analysis
At the time of excess pathology samples documenting response/relapse
Other: laboratory biomarker analysis
CSF generated at the time of each T-cell dose

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.