CMV-specific Cytotoxic T Lymphocytes Expressing CAR Targeting HER2 in Patients With GBM

NCT01109095 | Completed Phase 1 DMC

• 1 other identifier: H-24487 - HERT GBM
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

This study is for patients that have a type of brain cancer called glioblastoma multiforme (GBM). The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. The antibody used in this study is called anti-HER2 (Human Epidermal Growth Factor Receptor 2). This antibody sticks to GBM cells because of a substance on the outside of these cells called HER2. Up to 80% of GBMs are positive for HER2. HER2 antibodies have been used to treat people with HER2-positive cancers. For this study, the HER2 antibody has been changed so that instead of floating free in the blood it is now attached to T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These chimeric receptor-T cells seem to be able to kill tumors like GBM, but they don't last very long and so their chances of fighting the cancer are limited. Therefore, developing ways to prolong the life of these T cells should help them fight cancer. We found that T cells work better if we also attach a protein called CD28 to the HER2 chimeric receptor (HER2-CAR). In this study we placed this HER2-CAR into T cells that were pre-selected for their ability to recognize Cytomegalovirus (CMV). This virus exists in most people. These CMV-specific cytotoxic T cells (CMV-T cells) will be more active since they will react to the virus as well as to tumor cells. These HER2-CD28 CMV-T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of HER2-CD28 CMV-T cells, to learn what the side effects are, and to see whether this therapy might help patients with GBM.

Conditions

Glioblastoma Multiforme (GBM)

Keywords

Glioblastoma Multiforme (GBM); HER2; CMV; Brain Cancer; Autologous HER2.CAR CMV-specific cytotoxic CTL; CMV-specific cytotoxic CTL

Outcome Measures

Primary Outcomes (1)

• Number of subjects with dose limiting toxicity after CTL infusion

  To evaluate the safety of escalating doses of autologous CMV-specific cytotoxic T-lymphocytes (CTL) genetically modified to express chimeric antigen receptors (CAR) targeting the HER2 molecule in patients with HER2-positive Glioblastoma multiforme (GBM: WHO grade IV), who have recurrent or progressive disease after front line therapy.

  6 weeks

Secondary Outcomes (3)

• Decrease in tumor after the CTL infusion

  6 weeks

• Area under the growth curves (AUC) over time for T cell frequencies.

  15 years

• Impact of gene modified CTL on CMV-specific T lymphocyte immune response

  15 years

Study Arms (1)

HER.CAR CMV-specific CTLs

EXPERIMENTAL

Subject will be assigned a dose level at study entry.

Biological: HER.CAR CMV-specific CTLs

Interventions

HER.CAR CMV-specific CTLs BIOLOGICAL

HER2.CAR CMV-specific CTLs will be given by intravenous injection over 1-10 minutes through either a peripheral or a central line with a minimum 20g cannula. The patient will get one of the following doses: * 1 x 10\^6/m\^2 * 3 x 10\^6/m\^2 * 1 x 10\^7/m\^2 * 3 x 10\^7/m\^2 * 1 x 10\^8/m\^2

HER.CAR CMV-specific CTLs

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Histopathological verification of glioblastoma multiforme (GBM: WHO grade IV) with recurrent or progressive disease after front line therapy.
• HER2 positive GBM
• CMV seropositive
• Normal ECHO (Left ventricular ejection fraction (LVEF) has to be with in normal, institutional limits)
• Life expectancy 6 weeks or greater
• Karnofsky/Lansky score 50 or greater
• Patient or parent/guardian capable of providing informed consent
• Bilirubin 3x or less than normal, AST 5x or less than normal, creatinine 2x normal or less for age and Hgb 9.0 g/dl or more; WBC greater than 2,000/ul; ANC greater than 1,000/ul; platelets greater than 100,000/ul
• Pulse oximetry 90% or more on room air
• Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. The male partner should use a condom.
• Available autologous HER2.CAR-transduced CMV-specific cytotoxic T lymphocytes with 15% or greater expression of HER2.CAR determined by flow-cytometry and killing of HER2-positive targets 20% or more in cytotoxicity assay.
• Recovered from the acute toxic effects of all prior chemotherapy at least 4 weeks before entering this study. One exception is Temozolomide(TMZ), an alkylation agent used as a radiosensitizer and adjuvant chemotherapeutic agent for GBM. Due to the extremely short half life of TMZ, patients will be allowed to continue receiving it up to two days prior to cell infusion and cannot restart until six weeks after the infusion.

You may not qualify if:

• Severe intercurrent infection
• Known HIV positivity
• Pregnant or lactating
• History of hypersensitivity reactions to murine protein-containing products

Sponsors & Collaborators

• Baylor College of Medicine: lead
• The Methodist Hospital Research Institute: collaborator
• Center for Cell and Gene Therapy, Baylor College of Medicine: collaborator

Study Sites (2)

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Badhiwala J, Decker WK, Berens ME, Bhardwaj RD. Clinical trials in cellular immunotherapy for brain/CNS tumors. Expert Rev Neurother. 2013 Apr;13(4):405-24. doi: 10.1586/ern.13.23.

  PMID: 23545055 DERIVED

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Nabil Ahmed, MD

  Baylor College of Medicine - Texas Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: April 13, 2010
• First Posted: April 22, 2010
• Study Start: October 1, 2010
• Primary Completion: June 1, 2014
• Study Completion: March 7, 2018
• Last Updated: April 25, 2019

Record last verified: 2019-04

Locations

US (2)