Brain and Central Nervous System Tumors
Conditions
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
Brief 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.
Interventions
BIOLOGICALtherapeutic autologous lymphocytes
Cycles of escalating cell dose infusions up to the target cell dose of 10(8)
GENETICgene expression analysis
At the time of excess pathology samples documenting response/relapse
OTHERlaboratory biomarker analysis
CSF generated at the time of each T-cell dose
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Feasibility | 1 year after the end of treatment on study |
| Safety | 1 year after the end of treatment on study |
Secondary
| Measure | 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 |
Outcome results
None listed