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TGF-beta Resistant Cytotoxic T-lymphocytes in Treatment of EBV-positive Nasopharyngeal Carcinoma / RESIST-NPC

NCT02065362

Description:

Patients have nasopharyngeal carcinoma (NPC). This study is a gene transfer research study using special immune cells. Most patients with NPC show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of almost all patients with advanced stage NPC, suggesting that it may play a role in causing the disease. The cancer cells infected by EBV are able to hide from the body's immune system and escape destruction. We want to see if special white blood cells, called T cells, that have been trained to recognize and kill special parts of EBV infected cells can survive in patient's blood and affect the tumor. We already have given EBV-specific cytotoxic T cells to 30 patients with active NPC and have seen anti-tumor activity in 14 of 30 patients. We are now trying to find out if we can improve this treatment. First, we want to give T cells where more of the cells recognize at least two of the four EBV proteins expressed on NPC cells. We call these cells NPC-specific cytotoxic T cells. Second, we found that T cells work better if we add a receptor to the T cells called DNR (Dominant Negative Receptor). DNR makes T cells resistant to TGFbeta, a factor secreted by cancer cells that helps them escape being killed by the immune system. In this study we will therefore place the DNR gene into NPC-specific T cells (DNR.NPC-specific T cells). In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in their body, and potentially kill cancer cells more effectively. The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials.

Related Conditions:
  • Nasopharyngeal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

TGF-beta Resistant Cytotoxic T-lymphocytes in Treatment of EBV-positive Nasopharyngeal Carcinoma / RESIST-NPC

Title

  • Brief Title: TGF-beta Resistant Cytotoxic T-lymphocytes in Treatment of EBV-positive Nasopharyngeal Carcinoma / RESIST-NPC
  • Official Title: Administration Of TGF-beta Resistant Cytotoxic T-Lymphocytes to Patients With EBV-positive Nasopharyngeal Carcinoma (RESIST-NPC)
  • Clinical Trial IDs

    NCT ID: NCT02065362

    ORG ID: 33954: RESIST-NPC

    NCI ID: P01CA094237

    Trial Conditions

    EBV-positive Nasopharyngeal Carcinoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    Patients have nasopharyngeal carcinoma (NPC). This study is a gene transfer research study
    using special immune cells.

    Most patients with NPC show evidence of infection with the virus that causes infectious
    mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is
    found in the cancer cells of almost all patients with advanced stage NPC, suggesting that it
    may play a role in causing the disease. The cancer cells infected by EBV are able to hide
    from the body's immune system and escape destruction. We want to see if special white blood
    cells, called T cells, that have been trained to recognize and kill special parts of EBV
    infected cells can survive in patient's blood and affect the tumor.

    We already have given EBV-specific cytotoxic T cells to 30 patients with active NPC and have
    seen anti-tumor activity in 14 of 30 patients. We are now trying to find out if we can
    improve this treatment.

    First, we want to give T cells where more of the cells recognize at least two of the four
    EBV proteins expressed on NPC cells. We call these cells NPC-specific cytotoxic T cells.

    Second, we found that T cells work better if we add a receptor to the T cells called DNR
    (Dominant Negative Receptor). DNR makes T cells resistant to TGFbeta, a factor secreted by
    cancer cells that helps them escape being killed by the immune system. In this study we will
    therefore place the DNR gene into NPC-specific T cells (DNR.NPC-specific T cells).

    Detailed Description

    Blood will be collected from the patient to make LMP/BARF1/EBNA1 (NPC)-specific T cells. To
    grow NPC-specific T cells we have to use special cells called antigen-presenting cells,
    which train the patient's T cells to be NPC specific. Antigen presenting cells, so called
    monocytes or dendritic cells, will be grown/isolated from the patient's blood. In addition,
    we use a cell line called K562 as antigen-presenting cells that has had genes put inside it,
    which encourage the patient's T cells to grow. K562 cells are cancer cells. As such, if
    injected they could cause cancer. The cells have been treated with radiation so they cannot
    grow.

    These antigen-presenting cells are coated with a specially produced mixture of LMP, EBNA1
    and BARF protein fragments called peptides. These coated antigen-presenting cells are then
    used to generate the patient's NPC-specific T cells in the presence of growth factors. To
    get the DNR to attach to the surface of these NPC-specific T Cells, we also inserted the DNR
    gene into the NPC-specific T cells (DNR.NPC-specific T cells). This is done with a virus
    called a retrovirus that has been made for this study. This virus will carry the DNR gene
    into the cells.

    Once we have made sufficient numbers of DNR.NPC-specific T cells we will freeze the cells
    and test them to make sure they recognize EBV proteins present in NPC.

    Patients will get treated with two doses of DNR.NPC-specific T cells. The second dose will
    be given 2 weeks after the first dose.

    The T cells will be thawed and infused through a central line, or through a vein in the
    patient's arm over 1 to 10 minutes. Patients will be followed in the clinic after the
    infusion for 1 to 4 hours.

    All of the treatments will be given by the Center for Cell and Gene Therapy at Texas
    Children's Hospital or Houston Methodist Hospital.

    Medical tests before treatment:

    Before being treated, the patient will receive a series of standard medical tests:

    Physical exam Imaging Study Blood tests to measure blood cells, kidney and liver function
    Measurements of the tumor by routine imaging studies. We will use the imaging study that was
    used before to follow the patient's tumor: Computer Tomogram (CT), Magnetic Resonance
    Imaging (MRI), or Positron Emission Tomography (PET/CT)

    Medical tests during and after treatment:

    The patient will receive standard medical tests when they are getting the infusions and
    after:

    Physical exams Blood tests to measure blood cells, kidney and liver function Imaging study 8
    weeks after the 1st T-cell infusion

    To learn more about the way the DNR.NPC-specific T cells are working and how long they last
    in the body, an extra 60ml or 3ml/kg of body weight of blood (whichever is less) will be
    taken on the day of the T-cell infusion (before and at the end of the T-cell infusion), 1,
    2, 3, 4. 6, and 8 weeks after the T-cell infusion and every 3 months for 1 year, every 6
    months for 4 years, then yearly for a total of 15 years. One additional blood sample might
    be drawn 3 to 4 days post the 1st T-cell infusion; this is optional. This volume is
    considered safe, but may be decreased if the patient is anemic. In addition to the blood
    tests, the patient will receive 2 imaging studies as stated above.

    Trial Arms

    Name Type Description Interventions
    DNR.NPC-specific T cells Experimental Each patient will receive 2 infusions of DNR.NPC-specific T cells, 14 days apart.

    Eligibility Criteria

    Inclusion Criteria:

    The patient must meet the following eligibility inclusion criteria at the time of
    PROCUREMENT:

    - Nasopharyngeal Carcinoma in first or subsequent relapse or with primary refractory
    disease

    - EBV positive tumor

    - Informed consent explained to, understood by and signed by patient/guardian.
    Patient/guardian given copy of informed consent

    The patient must meet the following eligibility criteria to be included for TREATMENT:

    - Nasopharyngeal Carcinoma in first or subsequent relapse or with primary refractory
    disease

    - EBV positive tumor

    - Patients with life expectancy greater than or equal to 6 weeks

    - Bilirubin less than or equal to 3x upper limit of normal

    - AST less than or equal to 5x upper limit of normal

    - Hgb > 8.0g/dl (can be transfused)

    - Creatinine less than or equal to 2x upper limit of normal for age

    - Pulse oximetry of > 90% on room air

    - Off investigational therapy for 4 weeks prior to study entry

    - Karnofsky or Lansky score of greater than or equal to 50%

    - Sexually active patients must be willing to utilize one of the more effective birth
    control methods during the study and for 6 months after the study is concluded. The
    male partner should use a condom.

    - Informed consent explained to, understood by and signed by patient/guardian.
    Patient/guardian given copy of informed consent.

    Exclusion Criteria:

    At time of Procurement:

    Known HIV positivity

    At time of Treatment:

    - Pregnant or lactating

    - Severe intercurrent infection

    Minimum Eligible Age: N/A

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of subjects with a dose limiting toxicity

    Secondary Outcome Measures

    Amount of T cells in the blood after the infusions

    Trial Keywords

    EBV positive

    TGFbeta

    Nasopharyngeal carcinoma

    cytotoxic T lymphocytes