Clinical trial NCT00730613: Cellular Adoptive Immunotherapy Using Genetically Modified T-Lymphocytes in Treating Patients With Recurrent or Refractory High-Grade Malignant Glioma
Official title: Pilot Feasibility and Safety Study of Cellular Immunotherapy for Recurrent/Refractory Malignant Glioma Using Genetically-Modified Autologous CD8+ T Cell Clones
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
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
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-08-08
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Feasibility
timeFrame: 1 year after the end of treatment on study
measure: Safety
timeFrame: 1 year after the end of treatment on study
Secondary outcomes:
measure: Anti-tumor activity of adoptively transferred clones
timeFrame: 1 year after the end of treatment on study
measure: Anti-IL 13 zetakine and anti-HyTK immune response in patients
timeFrame: 1 year after the end of treatment on study
measure: Efficacy of ganciclovir for clone ablation (in the event of toxicity)
timeFrame: 1 year after the end of treatment on study
Other outcomes:
Locations:
Study officials:
affiliation: City of Hope Comprehensive Cancer Center
name: Stephen Forman, MD
role: PRINCIPAL_INVESTIGATOR
References: