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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pilot Feasibility and Safety Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Genetically-Modified Autologous CD8+ T Cell Clones

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Biological: therapeutic autologous lymphocytes
* Genetic: gene expression analysis
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (therapeutic autologous lymphocytes)<br>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. | Biological: therapeutic autologous lymphocytes<br>* Cycles of escalating cell dose infusions up to the target cell dose of 10(8)<br>Genetic: gene expression analysis<br>* At the time of excess pathology samples documenting response/relapse<br>Other: laboratory biomarker analysis<br>* CSF generated at the time of each T-cell dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility |  | 1 year after the end of treatment on study | 
| Safety |  | 1 year after the end of treatment on study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of adoptively transferred clones |  | 1 year after the end of treatment on study | 
| Anti-IL 13 zetakine and anti-HyTK immune response in patients |  | 1 year after the end of treatment on study | 
| Efficacy of ganciclovir for clone ablation (in the event of toxicity) |  | 1 year after the end of treatment on study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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