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

NCT ID: NCT00730613

Last Updated: 2017-10-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-02-28
• Study Completion Date: 2011-08-31

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.

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

therapeutic autologous lymphocytes

Intervention Type: BIOLOGICAL

Cycles of escalating cell dose infusions up to the target cell dose of 10(8)

gene expression analysis

Intervention Type: GENETIC

At the time of excess pathology samples documenting response/relapse

laboratory biomarker analysis

Intervention Type: OTHER

CSF generated at the time of each T-cell dose

Interventions

therapeutic autologous lymphocytes

Cycles of escalating cell dose infusions up to the target cell dose of 10(8)

Intervention Type: BIOLOGICAL

gene expression analysis

At the time of excess pathology samples documenting response/relapse

Intervention Type: GENETIC

laboratory biomarker analysis

CSF generated at the time of each T-cell dose

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen Forman, MD

Role: PRINCIPAL_INVESTIGATOR

City of Hope Comprehensive Cancer Center

Other Identifiers

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CHNMC-01020

Identifier Type: -

Identifier Source: secondary_id

CDR0000590506

Identifier Type: REGISTRY

Identifier Source: secondary_id

01020

Identifier Type: -

Identifier Source: org_study_id