Clinical Trials /

Most Closely HLA-Matched CTLs for Relapsed Epstein Barr Virus(EBV)-Associated Diseases

NCT01447056

Description:

Patients have a type of a lymph node cancer called lymphoma, a tumor of the nasal passages called nasopharyngeal carcinoma (NPC), a tumor of a particular type of muscle called leiomyosarcoma (LMS) or a condition called severe chronic active EBV (SCAEBV) syndrome. The disease has come back, may come back or has not gone away after treatment. This voluntary research study uses special immune system cells called LMP-specific cytotoxic T lymphocytes, a new experimental therapy. Some patients with these diseases show evidence of infection with the virus that causes infectious mononucleosis (called Epstein-Barr virus, or EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of up to half of the patients with lymphomas, and in some cases of NPC and LMS, suggesting that it may play a role in causing these diseases. Those cancer cells (as well as some B cells in SCAEBV) that are 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 kill cells infected by EBV can survive in the blood and affect the tumor. This treatment with specially trained T cells has had activity against these viruses when the cells are made from patients with those diseases (or, after bone marrow transplant, from the patient's transplant donor). However, sometimes it is not possible to grow these cells; other times, it may take 2 to 3 months to make the cells, which may be too long when one has an active tumor. We are therefore asking if subjects would like to participate in this study, which tests if blood cells from a donor that is a partial match with the subject (or the transplant donor) that have been grown in the way described above can survive in the blood and affect the disease. These LMP-specific CTLs are an investigational product not approved by the Food and Drug Administration.

Related Conditions:
  • Cancer
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Most Closely HLA-Matched CTLs for Relapsed Epstein Barr Virus(EBV)-Associated Diseases

Title

  • Brief Title: Most Closely HLA-Matched CTLs for Relapsed Epstein Barr Virus(EBV)-Associated Diseases
  • Official Title: Most Closely HLA-Matched Allogeneic LMP1/2-Specific Cytotoxic T Lymphocytes for Treatment of Patients With Relapsed EBV-Associated Diseases
  • Clinical Trial IDs

    NCT ID: NCT01447056

    ORG ID: H-28361-MALTED

    NCI ID: MALTED

    Trial Conditions

    Hodgkin Lymphoma

    Non-Hodgkin Lymphoma

    Lymphoproliferative Disorder

    Nasopharyngeal Carcinoma

    Leiomyosarcoma

    Severe Chronic Active EBV (SCAEBV)

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    Patients have a type of a lymph node cancer called lymphoma, a tumor of the nasal passages
    called nasopharyngeal carcinoma (NPC), a tumor of a particular type of muscle called
    leiomyosarcoma (LMS) or a condition called severe chronic active EBV (SCAEBV) syndrome. The
    disease has come back, may come back or has not gone away after treatment. This voluntary
    research study uses special immune system cells called LMP-specific cytotoxic T lymphocytes,
    a new experimental therapy.

    Some patients with these diseases show evidence of infection with the virus that causes
    infectious mononucleosis (called Epstein-Barr virus, or EBV) before or at the time of their
    diagnosis. EBV is found in the cancer cells of up to half of the patients with lymphomas,
    and in some cases of NPC and LMS, suggesting that it may play a role in causing these
    diseases. Those cancer cells (as well as some B cells in SCAEBV) that are 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 kill cells infected by
    EBV can survive in the blood and affect the tumor.

    This treatment with specially trained T cells has had activity against these viruses when
    the cells are made from patients with those diseases (or, after bone marrow transplant, from
    the patient's transplant donor). However, sometimes it is not possible to grow these cells;
    other times, it may take 2 to 3 months to make the cells, which may be too long when one has
    an active tumor. We are therefore asking if subjects would like to participate in this
    study, which tests if blood cells from a donor that is a partial match with the subject (or
    the transplant donor) that have been grown in the way described above can survive in the
    blood and affect the disease.

    These LMP-specific CTLs are an investigational product not approved by the Food and Drug
    Administration.

    Detailed Description

    First, we will search our cell bank to see if there is a CTL line that is a match with the
    subject and his/her donor. This matching is done using HLA type, which measures 6 proteins
    on the cell surface. If HLA type has not been previously checked, we will do a blood draw
    (half to one tablespoon) so that this can be done.

    These CTL lines have been made at Baylor College of Medicine from donors for other
    transplant patients or other normal donors from the National Marrow Donor Program. All
    donors have been screened in the same way that we screen blood donors. When the CTL lines
    were made, blood was taken from the donors and used to grow T cells. To do this, we first
    grew a special type of cells called dendritic cells or monocytes and we put a specially
    produced human virus (adenovirus) that carries the LMP genes into the dendritic cells or
    monocytes. They were then used to stimulate T cells. This stimulation trained the T cells to
    kill cells with LMP on their surface.

    We then grew these LMP specific CTLs by more stimulation with EBV infected cells (made from
    the same blood). We also put the adenovirus that carries the LMP genes into these EBV
    infected cells so that we increased the amount of LMP that these cells had. These EBV
    infected cells were treated with radiation so they could not grow. Once we made sufficient
    numbers of T cells, we tested them to make sure they kill cells with LMP on their surface
    and froze them.

    To make sure that these cells won't attack the subject's tissues, we will also test the
    cells against his/her own cells, which we will grow in the laboratory.

    If the level of circulating T-cells in the patient is relatively high, s/he will receive one
    treatment of cyclophosphamide. This drug will decrease the numbers of the patient's own
    T-cells before the investigators infuse the LMP-specific cytotoxic T-lymphocytes. If the
    patient is already receiving chemotherapy, this may not be needed.

    The LMP specific CTLs will be thawed and injected IV over 1-5 minutes. Initially, one dose
    of T-cells will be given. If after the first dose, there is a reduction in the size of the
    patient's disease, they can receive up to five additional doses of the T-cells if they wish.

    This is a dose escalation study, which means that the doses of cells will be increased as
    more patients are treated, as long as the lower doses are determined to be safe.

    Trial Arms

    Name Type Description Interventions
    LMP Specific T cells Experimental LMP specific T cells will be given by intravenous injection over 1-10 minutes through either a peripheral or a central line and the IV flushed with saline. Then the second product will be given by intravenous injection over 1 to 10 minutes and the IV flushed with saline. The volume of infusion will depend upon the concentration of the cells when frozen, the dose level, and the size of the patient.

    Eligibility Criteria

    INCLUSION CRITERIA:

    SCREENING:

    1. Any patient, regardless of age or sex, with one or more of the following EBV-positive
    or associated disorders, regardless of the histological subtype: - Hodgkin lymphoma -
    Non-Hodgkin lymphoma - Lymphoproliferative disorder - Nasopharyngeal carcinoma -
    Leiomyosarcoma - Severe chronic active EBV infection syndrome (SCAEBV), defined as
    high EBV viral load in plasma or PBMC (> 4000 genomes per ug PBMC DNA) and/or biopsy
    tissue positive for EBV

    2. Karnofsky/Lansky score 50% or more.

    3. Informed consent explained to and signed by patient or parent/guardian able to give
    informed consent and given a copy.

    TREATMENT:

    1. Any patient, regardless of age or sex, with one or more of the following EBV-positive
    or associated disorders, regardless of the histological subtype: - Hodgkin lymphoma -
    Non-Hodgkin lymphoma - Lymphoproliferative disorder - Nasopharyngeal carcinoma -
    Leiomyosarcoma - Severe chronic active EBV infection syndrome (SCAEBV), defined as
    high EBV viral load in plasma or PBMC (> 4000 genomes per ug PBMC DNA) and/or biopsy
    tissue positive for EBV

    2. The disease needs to be in one of the following stages: - At diagnosis or in first
    relapse AND the patient is unable to receive conventional chemotherapy for his/her
    condition. - In second or subsequent relapse. - With residual disease after
    autologous, syngeneic or allogeneic HSCT.

    3. Life expectancy 6 weeks or more.

    4. Tumor tissue is positive for EBV.

    5. Karnofsky/Lansky score 50% or more.

    6. Bilirubin less than 3 less than upper limit of normal (ULN), AST less than 5 less
    than ULN, Hgb greater than 8.0 g/dL and serum creatinine less than 3 less than ULN

    7. Pulse oximetry of greater than 90% on room air.

    8. If post allogeneic HSCT, patient must not have less than 50% donor chimerism in
    either peripheral blood or bone marrow.

    9. Clinical status at enrollment to allow tapering of steroids to less than 0.5
    mg/kg/day prednisone at time of treatment.

    10. Informed consent explained to and signed by patient or parent/guardian able to give
    informed consent and given a copy.

    11. Sexually active patients must be willing to utilize one of the more effective birth
    control methods during the study and for 3 months after the study is concluded. The
    male partner should use a condom.

    EXCLUSION CRITERIA:

    SCREENING:

    1. Known HIV positivity.

    TREATMENT:

    1. Currently receiving any investigational agents or have received any tumor vaccines
    within previous 4 weeks.

    2. Active acute grade III-IV graft-versus-host disease.

    3. Severe intercurrent infection.

    4. Received alemtuzumab or other anti-T-cell antibody within 28 days.

    5. HIV seropositivity.

    6. Pregnancy (due to unknown effects of this therapy on a fetus) or lactation.

    7. Tumor in a location where enlargement could cause airway obstruction.

    Minimum Eligible Age: N/A

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Patients with dose limiting toxicities after T-cell infusions

    Secondary Outcome Measures

    Safety and response to a repeated dosage regimen

    Analysis of immune function of CTLs

    Number of patients with an EBV and/or disease response to the CTLs

    Trial Keywords

    Hodgkin lymphoma

    Non-Hodgkin lymphoma

    Lymphoproliferative disorder

    Nasopharyngeal carcinoma

    Leiomyosarcoma

    EBV Cytotoxic T Lymphocytes