Clinical Trials /

Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

NCT01498484

Description:

This is a Phase II trial to evaluate the efficacy and safety of human leukocyte antigen (HLA) partially-matched third-party allogeneic Epstein-Barr virus cytotoxic T lymphocytes (EBV-CTLs) for the treatment of EBV-induced lymphomas and EBV-associated malignancies.

Related Conditions:
  • Cancer
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

Title

  • Brief Title: Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies
  • Official Title: A Phase II Study of The Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies
  • Clinical Trial IDs

    NCT ID: NCT01498484

    ORG ID: 11-130

    Trial Conditions

    Non-Hodgkin's Lymphoma

    Epstein-Barr Virus

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    This study is testing to see how well transfusions of T-cells work in treating Epstein-Barr
    Virus (EBV). These T-cells are made from the blood of normal donors who are immune to EBV. A
    transfusion is the process by which blood from one person is transferred to the blood of
    another. In this case the investigators are transferring Tcells. T-cells are a type of white
    blood cell that helps protect the body from infection.

    Researchers have already seen complete and lasting remissions of EBV in a small group of
    bone marrow transplant recipients by giving them T-cells from their transplant donors. The
    T-cells are immune to EBV. A remission means a person's disease has gotten better. Based on
    this, researchers have been running a larger trial to see whether EBV-immune T-cells can
    help patients who have EBV without causing bad reactions. So far, they have not seen any
    patients get bad reactions from infusions of EBV-immune T-cells. Some patients who get EBV
    may respond to EBV-immune T-cells from donors other than their transplant donors. These
    donors are called "third party donors". Researchers use third party donors when they cannot
    make EBV-immune T-cells from the original transplant donor or if the patient did not receive
    a transplant. If the patient consents to this trial, the EBV-immune T-cells made from a
    third party donor will be used to treat and possibly cure their EBV disease. The patient
    will get at least three weekly transfusions of these cells on this trial.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Group 1 Experimental Group 1 will consist of: A. Allogeneic marrow graft recipients who are severely immunocompromised and may have more prolonged or sustained T cell engraftment and, therefore, could be at risk for GvHD B. Patients with severe congenital or antineoplastic drug induced immunodeficiency who could be durably engrafted and are therefore at risk for GvHD
    Group 2 Experimental Group 2 will consist of: A. Organ allograft recipients. Although immunocompromised, these patients can reject third party blood cells. Thus, the risk of sustained engraftment or GvHD is low B. AIDS patients who will almost invariably reject the infused T-cells and are therefore at very low risk of GvHD C. Patients who develop other EBV-associated malignancies without pre-existing immune deficiency who are also expected to reject the infused T cells and are at low or no risk of GvHD

    Eligibility Criteria

    Inclusion Criteria:

    - Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma
    or other EBVassociated malignancy.

    OR

    - Evaluable disease as demonstrated by clinical and/or radiologic studies with current
    or prior elevated blood levels of EBVDNA exceeding 500 copies/ml by quantitative real
    time pcr.

    OR

    - Persistent or recurrent elevations in levels of EBVDNA exceeding 500 copies/ml in
    patients previously treated for EBVLPD with chemotherapy and/or Rituxan who do not
    yet have clinically or radiologically evaluable disease but are at high risk of
    disease recurrence.

    - EBV-specific T-cells from donor of the patient's transplant are not available.

    - EBV-specific T-cells are available for adoptive immune cell therapy from a consenting
    third party donor. The third party EBV CTLs to be administered will be selected on
    the basis of two criteria: 1) that they are matched for at least 2 HLA antigens and
    2) that they are restricted by an allele shared with the EBV+ malignancy (if known),
    or with the donor in HSCT recipients, or patient in organ transplant or
    immunodeficient patients

    - KPS or Lansky score 20.

    - A life expectancy of at least 6 weeks.

    - Adequate bone marrow, heart, lung, liver and kidney function at the time treatment
    with EBV-specific

    - T-cells is initiated, including:

    1. Absolute neutrophil count (ANC) 1K/mcL, with or without GCSF support

    2. Platelets 20,K/mcL

    3. Creatinine 2.0mg/dl

    4. ALT, AST < 3.0x and total bilirubin < 2.5x the institutional ULN

    5. Stable blood pressure and circulation not requiring pressor support

    6. Adequate cardiac function as demonstrated by EKG and/or echocardiographic
    evidence (may be performed within 30 days prior to treatment)

    - However, abnormalities of specific organs will not be considered grounds for
    exclusion if they are the result of the EBV+ malignancy or its treatment (e.g. a
    renal allograft recipient with an EBVLPD may be on dialysis because the allograft was
    rejected when the immune suppression was stopped as a first approach to treatment of
    the EBVLPD). At the discretion of the investigator, patients with elevated but stable
    creatinine will not be precluded from treatment on study.

    - There is no age restriction to eligibility for this protocol.

    - It is expected that five types of patients afflicted with EBV-associated lymphomas,
    lymphoproliferative diseases or malignancies will be referred and will consent to
    participate in this trial. These are:

    - Patients developing EBV lymphomas or lymphoproliferative disorders following an
    allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie: marrow, PBSC, or
    umbilical cord blood). In these cases, the HSCT donor, if EBV-seropositive, will be
    used as the donor of EBV-specific T-cells for adoptive immunotherapy wherever
    possible, because the EBV-LPD are almost invariably derived from that marrow donor.
    These patients will be enrolled onto protocol # IRB 95-024. However, if the HSCT
    donor is EBV seronegative or not readily available (e.g. a cord blood transplant),
    the patient will be a candidate to receive EBV- specific T-cells generated from a
    third party seropositive donor that have been generated and stored in the MSKCC bank
    of cryopreserved immune T-cells for adoptive cell therapy. For these patients, the
    third party donor derived T cells to be used will be selected primarily on the basis
    of matching for 2 HLA alleles shared by the transplant donor and recipient. However,
    priority is given to T cells partially matched with, and restricted by, HLA alleles
    of the transplant donor, since EBV + lymphomas in HSCT recipients are usually (but
    not always) derived from the transplant donors' cells.

    - Patients developing EBV lymphomas or lymphoproliferative disorders following an
    allogeneic organ transplant. In these cases, the lymphoma is usually of recipient
    origin. EBV-specific T-cells will be selected from the MSKCC Bank expanded from an
    EBV-seropositive normal donor who is at least matched for 2 HLA alleles with the EBV
    lymphoma. If the origin of the lymphoma is unknown, T-cells partially matched with
    the transplant recipient will be used, since these lymphomas are usually of host
    origin. Using this approach to donor selection, it is expected that the EBV-specific,
    HLA restricted cytotoxic T-cells expanded from the HLA partially-matched donor would
    be able to recognize and kill lymphoma cells presenting EBV antigens in the context
    of an appropriate HLA restricting element. Priority will be given to the use of
    partially matched EBV specific T cells known to be restricted by an HLA allele shared
    by the lymphoma (or, if unknown, the patient).

    - Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a
    consequence of the profound acquired immunodeficiency induced by HIV. For such
    patients, EBV specific T-cells from third party seropositive donors who are HLA
    compatible in at least 2 HLA alleles shared by the patient will be used.

    Selection of T cells known to be restricted by an HLA allele shared by the patient will be
    given priority.

    - Patients who develop EBV lymphomas or lymphoproliferative diseases or other
    EBV-associated malignancy as a consequence of profound immunodeficiencies associated
    with a congenital immune deficit or acquired as a sequela of anti-neoplastic or
    immunosuppressive therapy. For these patients, normal, EBV specific T-cells from
    third party seropositive donors who are HLA compatible in at least 2 HLA alleles
    shared by the patient will be used. Again, selection of T cells known to be
    restricted by an HLA allele shared by the patient will be given priority.

    - Patients who develop other EBV-associated malignancies without pre-existing immune
    deficiency, including: EBV+ Hodgkin's and Non-Hodgkin's disease, EBV+ nasopharyngeal
    carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma. Normal,
    EBV specific T-cells from third party seropositive donors who are HLA compatible in
    at least 2 HLA alleles shared by the patient will be used. Again, selection of T
    cells known to be restricted by an HLA allele shared by the patient will be given
    priority.

    Donor Eligibility

    - Donors in Groups 1 and 2 (Section 5.1) would have already been determined to be
    eligible and will have donated blood or leukocytes to establish EBV-specific T-cells
    under IRB # 05-065, 07-055, 95-024 or 12-086. There are no additional eligibility
    requirements for these donors.

    - Donors in Group 3 (section 5.1), however, will need to meet the following eligibility
    requirements prior to donation:

    - Donors must satisfy the criteria specified in FDA 21 CFR 1271 Donors must be typed
    for HLA-A, B, C and DR

    - Donors must have a hemoglobin value > 10g/dl

    - Donors must be capable of undergoing, at least, a single standard 2 blood volume
    leukapheresis or a donation of one unit of whole blood

    Exclusion Criteria:

    Patient Exclusion Criteria

    The following patients will be excluded from this study:

    - Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or
    an overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of
    glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment

    - Patients who are pregnant

    - Patients with severe comorbidities, not related to their EBV-associated malignancy,
    that would be expected to preclude their survival for the 6 weeks required to assess
    response of T cell therapy Donor Exclusion Criteria

    - HTLV/HIV(+) or Hepatitis B or C antigen(+) donors

    - Donors who are known EBV seronegative

    Minimum Eligible Age: N/A

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    efficacy

    Secondary Outcome Measures

    remaining EBV-LPD free

    Trial Keywords

    EBV-specific T-cell lines

    11-130