Evaluation of Recovery From Drug-Induced Lymphopenia Using Cytomegalovirus-specific T-cell Adoptive Transfer

NCT00693095 | Completed Phase 1 DMC

• 2 other identifiers: Pro00000580SPORE Project 3
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to learn if your own immune cells can be activated and multiplied in order to help your body fight off the tumor cells in your brain. The safety of this procedure will also be studied. This procedure, called CMV-autologous lymphocyte transfer or CMV-ALT is investigational which means that it is not approved by the US Food and Drug Administration (FDA) and is still being tested in research studies. Autologous lymphocyte transfer or ALT means that you will receive your own immune cells back (and not from another donor) as a treatment after they have been activated and grown to large numbers in a clinical lab. It is believed that the body's immune (protection) system can attack tumor cells and kill them. Immune cells called T-lymphocytes (T-cells) can recognize special proteins on the surface of tumors as a signal to attack and fight the cancer. In most patients with advanced cancer, the immune system does not adequately destroy the tumor because the white blood cells or T-cells are not stimulated enough. Before your T-cells can become active against tumor cells, they require strong stimulation. There are special "stimulator" cells in the body called Dendritic Cells (DCs) that can take up proteins released from cancer cells and present pieces of these proteins to T lymphocytes to create this strong stimulation. Dendritic cells taken from your blood will be "pulsed" or loaded with genetic material called RNA (ribonucleic acid), which stimulates the DC to change the RNA into a protein called pp65. This protein is produced by a common virus called Cytomegalovirus (CMV) that 70-80% of us have been exposed to in our lifetime. Recently, we have found that this virus is present in many malignant brain tumors. Brain tumors are very aggressive and, for reasons we do not yet understand, are difficult for the body to attack. The CMV virus is a target in the tumor that, if attacked by your immune systems cells, may prevent your tumor from growing. We have found that we can grow immune cells to very large numbers from the blood of people who have evidence of prior exposure to this virus. You will therefore be tested to determine if you have pre-existing antibodies to this virus in order to participate in this study. We will use your DCs to activate and grow immune cells from your blood to large numbers in a clinical laboratory. These CMV-specific immune cells, called CMV-ALT, will be returned to your body when they have become activated. It is hoped that these cells will seek out and kill tumor cells that express the CMV viral protein and not attack normal cells. The transfer of immune cells that stimulates your immune system is called adoptive immunotherapy. We will evaluate two doses of immune cells in this study (Dose 1 and Dose 2). Depending on when you are enrolled in this study you will receive either Dose 1 or 2. The first six patients enrolled on this study will receive Dose 1 (the lower dose) and the next six patients will receive Dose 2 (the higher dose). We do not know at this time if either dose is more effective or safer to administer which is why we are testing both doses. Dose 2 will be a larger number of immune cells if the treatment is found to be safe in the first six patients treated during this study. In this study we will also see, in some randomly selected patients, if giving an injection of the DC pulsed with pp65 RNA into the skin improves the function of the CMV-ALT treatment or not. You will receive three injections under the skin of either some of the same DC that were used to stimulate your immune cells in the clinical laboratory or three injections of saline (salt solution) under the skin starting with the infusion of the CMV-ALT. It is unknown if a DC injection will be beneficial to the immune cells or not so the responses will be compared in patients who receive DC versus saline injection with their CMV-ALT. After these three injections, blood will be collected to compare the responses between patients that received saline to those that received DC injections.

Conditions

Glioblastoma

Keywords

Grade IV Glioblastoma Multiforme; Newly-diagnosed; CMV positive

Outcome Measures

Primary Outcomes (1)

• To evaluate if vaccinating adult patients with newly-diagnosed GBMs using CMV-DCs during recovery from therapeutic TMZ-induced lymphopenia with ALT in patients that are seropositive for CMV enhances the T-cell response.

  4 months after enrollment

Secondary Outcomes (1)

• To evaluate the safety of ALT with CMV pp65-activated T-cells in adult patients with newly-diagnosed GBMs during recovery from therapeutic TMZ-induced lymphopenia.

  4 months from time of enrollment

Study Arms (2)

1

EXPERIMENTAL

CMV-ALT + CMV-DCs

Biological: CMV-ALT + CMV-DCs

2

EXPERIMENTAL

CMV-ALT + Saline

Biological: CMV-ALT + Saline

Interventions

CMV-ALT + CMV-DCs BIOLOGICAL

CMV-ALT (3 X 10e7) with CMV-DCs (2 X 10e7)

1

CMV-ALT + Saline BIOLOGICAL

CMV-ALT (3 X 10e7) with Saline

2

Eligibility Criteria

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

You may qualify if:

• Age \>18 years of age.
• GBM (WHO Grade IV) with definitive resection \<4 weeks prior to leukapheresis with residual radiographic contrast enhancement on post-resection CT or MRI of \<1 cm in maximal diameter in any axial plane.
• Karnofsky Performance Status (KPS ) of \> 80% and a Curran Group status of I-IV.

You may not qualify if:

• Radiographic or cytologic evidence of leptomeningeal or multicentric disease at any time prior to vaccination.
• Prior conventional anti-tumor therapy other than steroids, RT, or TMZ.
• Pregnant or need to breast feed during the study period (Negative b-HCG test required).
• Requirement for continuous corticosteroids above physiologic levels at time of first vaccination.
• Active infection requiring treatment or an unexplained febrile (\> 101.5o F) illness.
• Known immunosuppressive disease or human immunodeficiency virus infection.
• Patients with unstable or severe intercurrent medical conditions such as severe heart or lung disease.
• Allergic or unable to tolerate TMZ for reasons other than lymphopenia.
• Patients with previous inguinal lymph node dissection.

Sponsors & Collaborators

• John Sampson: lead

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (1)

• Reap EA, Suryadevara CM, Batich KA, Sanchez-Perez L, Archer GE, Schmittling RJ, Norberg PK, Herndon JE 2nd, Healy P, Congdon KL, Gedeon PC, Campbell OC, Swartz AM, Riccione KA, Yi JS, Hossain-Ibrahim MK, Saraswathula A, Nair SK, Dunn-Pirio AM, Broome TM, Weinhold KJ, Desjardins A, Vlahovic G, McLendon RE, Friedman AH, Friedman HS, Bigner DD, Fecci PE, Mitchell DA, Sampson JH. Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma. Cancer Res. 2018 Jan 1;78(1):256-264. doi: 10.1158/0008-5472.CAN-17-0469. Epub 2017 Nov 1.

  PMID: 29093005 BACKGROUND

Related Links

• Brain Tumor Center of Duke University Medical Center

MeSH Terms

Conditions

Glioblastoma

Interventions

Sodium Chloride

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

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Gordana Vlahovic, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor Neurosurgery

Study Record Dates

• First Submitted: June 3, 2008
• First Posted: June 6, 2008
• Study Start: September 1, 2008
• Primary Completion: December 1, 2013
• Study Completion: April 1, 2015
• Last Updated: January 30, 2018

Record last verified: 2018-01

Locations

US (1)