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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00730613
• Other study ID #: 01020
• Secondary ID: P30CA033572CHNMC
• Status: Completed
• Phase: Phase 1
• First received: August 7, 2008
• Last updated: October 6, 2017
• Start date: February 2002
• Est. completion date: August 2011

Study information

• Verified date: October 2017
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: August 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Glioma
• Nervous System Neoplasms

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility		1 year after the end of treatment on study
Primary	Safety		1 year after the end of treatment on study
Secondary	Anti-tumor activity of adoptively transferred clones		1 year after the end of treatment on study
Secondary	Anti-IL 13 zetakine and anti-HyTK immune response in patients		1 year after the end of treatment on study
Secondary	Efficacy of ganciclovir for clone ablation (in the event of toxicity)		1 year after the end of treatment on study