Clinical Trial Finder

DISEASE CHARACTERISTICS:

• - Histologically confirmed malignant glioma at original diagnosis.

• - Grade III or IV disease.

• - Refractory or recurrent disease.

• - Unifocal site of original disease in cerebral cortex.

• - No clinical evidence of progressive encephalopathy.

• - Has not undergone recent re-resection of recurrent or progressive disease.

• - No communication between the tumor resection cavity and the ventricles and deep cerebrospinal fluid pathways as documented by post-operative MRI scan.

PATIENT CHARACTERISTICS:

• - Karnofsky performance status 70-100% - Life expectancy > 3 months.

• - WBC ≥ 2,000/dL.

• - ANC > 1,000/dL.

• - Platelet count ≥ 100,000/dL (unsupported by transfusion or growth factor) - Creatinine < 1.6 mg/dL.

• - Bilirubin < 1.5.

• - SGOT and SGPT < 2 times upper limit of normal.

• - Not pregnant.

• - Negative pregnancy test.

• - Fertile patients must use effective contraception.

• - Able to understand protocol basic elements and/or risks/benefits of participating in this pilot study.

• - No requirement for supplemental oxygen to keep saturation > 95% that is not expected to resolve within 2 weeks.

• - No uncontrolled cardiac arrhythmia.

• - No hypotension requiring pressor support.

• - No renal dialysis dependency.

• - No refractory seizure disorder.

• - No concurrent non-malignant illness that is poorly controlled with treatment or is of such severity the investigators deem it unwise to enter the patient on protocol.

• - No severe infection for which patient is being treated.

• - No history of ganciclovir and/or Prohance contrast allergy or intolerance.

• - No HIV positivity within the past 3 months.

PRIOR CONCURRENT THERAPY:

• - See Disease Characteristics.

• - Must have recovered from major surgery.

• - At least 4 weeks since primary therapy and no steroid dependence.

• - At least 2 weeks since prior adjuvant cytotoxic chemotherapy and recovered.

• - No concurrent systemic corticosteroids, except for use in managing T-cell therapy toxicity.

• - No concurrent immunotherapy (i.e., interferons, vaccines, or other cellular products) - No concurrent pentoxifylline.

• - No other concurrent investigative agents.

• - No concurrent ganciclovir or ganciclovir derivative.

- No concurrent acyclovir for non-life threatening herpes virus infection

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.

Arms

Experimental: Treatment (therapeutic autologous lymphocytes)

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.

Interventions

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