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

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

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.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Biological: therapeutic autologous lymphocytes; Genetic: gene expression analysis; Other: laboratory biomarker analysis

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephen Forman, MD, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: February 1, 2002
• Primary Completion (ACTUAL): August 1, 2011
• Study Completion (ACTUAL): August 1, 2011

Study Registration Dates

• First Submitted: August 7, 2008
• First Submitted That Met QC Criteria: August 7, 2008
• First Posted (ESTIMATE): August 8, 2008

Study Record Updates

• Last Update Posted (ACTUAL): October 9, 2017
• Last Update Submitted That Met QC Criteria: October 6, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor; adult anaplastic astrocytoma; adult anaplastic ependymoma; adult anaplastic oligodendroglioma; adult brain stem glioma; adult diffuse astrocytoma; adult ependymoma; adult myxopapillary ependymoma; adult oligodendroglioma; adult subependymoma; adult mixed glioma; adult pilocytic astrocytoma; adult subependymal giant cell astrocytoma; adult pineal gland astrocytoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms
• Other Study ID Numbers: 01020; P30CA033572 (U.S. NIH Grant/Contract); CHNMC-01020; CDR0000590506 (REGISTRY: NCI PDQ)